Rerouting therapeutic peptides and unlocking their potential against SARS-CoV2.

The COVID-19 pandemic highlighted the potential of peptide-based therapies as an alternative to traditional pharmaceutical treatments for SARS-CoV-2 and its variants. Our review explores the role of therapeutic peptides in modulating immune responses, inhibiting viral entry, and disrupting replication. Despite challenges such as stability, bioavailability, and the rapid mutation of the virus, ongoing research and clinical trials show that peptide-based treatments are increasingly becoming integral to future viral outbreak responses. Advancements in computational modelling methods in combination with artificial intelligence will enable mass screening of therapeutic peptides and thereby, comprehending a peptide repurposing strategy similar to the small molecule repurposing. These findings suggest that peptide-based therapies play a critical and promising role in future pandemic preparedness and outbreak management.

Peptide repurposing, SARS-CoV-2, Peptide inhibitors, Antiviral peptides, Multipurpose peptides, Immunomodulatory peptides, Sustainable Development Goals

SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus 2 also known as SARS-CoV-2, is a contagious virus that instigated its pattern of infecting people in late 2019, thus leading to the COVID-19 pandemic. SARS-CoV-2 first infects the lower airways by binding to ACE2 in alveolar epithelial cells (Singh et al. 2020). It is most likely originated from bats while studies are still on to identify intermediate hosts (Banerjee et al. 2021). The first reported case of SARS was detected in Foshan, China, in November 2002, with the virus quickly spreading to Wuhan, China (Spiteri et al. 2020). In February 2003, over 300 cases had been documented, with around one-third involving healthcare personnel. New cases continued to appear in mainland China (N. Lee et al. 2003). Early in April of that year, the SARS coronavirus was identified due to an incredible international effort (Peiris et al. 2003). By July 2003, 8,096 cases were reported worldwide, with 774 of those cases resulting in deaths (Cherry 2004). Since December 2003 – January 2004, about 2,502 confirmed cases and 861 deaths (or 34.4% mortality rate) were reported in 27 countries between April 2012 and December 2019 (WHO EMRO, 2019). However, the COVID-19 pandemic far exceeded previous coronavirus outbreaks, prompting the World Health Organization (WHO) to declare SARS-CoV-2 a Public Health Emergency of International Concern on January 30, 2020 (Cucinotta and Vanelli 2020). Exceptionally high transmissibility and wider geographic spread of this latest SARS-CoV-2 exceeded those of earlier coronaviruses such as SARS and MERS (Schwab et al. 2023). The primary cause of this was respiratory droplets and aerosols released during talking, sneezing, and coughing (Stadnytskyi et al. 2021). The virus enhances the entry and subsequent infection in human cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor. Symptoms of COVID-19 infection commonly manifest after an incubation period, roughly about 5 days, though it may range between 3 and 14 days (Li et al. 2020), (Lu et al. 2020). Besides, the time interval from the onset of symptoms to mortality among dead individuals varied from 6 to 41 days, with a median of 14 days (W. Wang et al. 2020). As already known, COVID-19 can be asymptomatic or present mildly, from simple respiratory problems to more serious manifestations of pneumonia and acute respiratory distress syndrome (Hu et al. 2020). Rapid emergence causes global outbreaks, high morbidity, mortality, and adverse effects (Kurrey and Saha 2022) (Rothan and Byrareddy 2020). Like other coronaviruses, SARS-CoV-2 comprises four structural proteins and a number of non-structural proteins. These structural proteins were identified to be the nucleocapsid, membrane, spike, and envelope proteins. The viral envelope is composed of the combined effort of the S, E, and M proteins (Wu et al. 2020). The spike protein binds human angiotensin-converting enzyme-2 (hACE2) in respiratory tracts for viral attachment (Du et al. 2009). During the peak pandemic era, several SARS-CoV-2 variations were reported; however, only a small number of these were classified as variants of concern (VOCs) (Carabelli et al. 2023). The WHO’s epidemiological report states that five SARS-CoV-2 VOCs have been identified since the epidemic began. [Fig. 1]. Peptide therapeutics: general overview History and evolution of peptide as drugs Peptides are identified as a distinct class of pharmaceutical compounds, showcasing biochemical and therapeutic differences from both proteins and small molecules, while being molecularly located between them. Therapeutic peptide research began with studying natural human hormones such as insulin, oxytocin, vasopressin, and GnRH, and their physiological activities in the human body (Craik et al. 2013). Peptide-based therapies are characterized by various advantages over conventional small-molecule drugs, such as high specificity, low toxicity, and quick adaptation to emerging new viral variants (Singh et al. 2020). Since 1921, over 80 peptide-based medications have been approved globally, including insulin and adrenocorticotropic hormone (L. Wang et al., 2022a), (Diem et al. 2022). In 2012, peptide therapeutics experienced significant growth, resulting in the first marketing approvals for six new molecular entities in a single year, particularly glucagon-like-peptide-1 receptor agonists like liraglutide (Kaspar and Reichert 2013). Peptide therapies have high specificity, low toxicity, and rapid adaptation to new viral variants, making them promising for SARS-CoV-2 targeting in a rapidly evolving pandemic. The use of peptides as therapeutic agents evolved over time and continues to develop along with the emergence of new approaches to both their synthesis and modern methods of treatment (Ivanov and Deigin 2023). Currently, the global pharmaceutical industry has registered about 5000 therapeutic compounds derived from natural and synthetic organic molecules, of which approximately 80 are peptide-based (Ivanov and Deigin 2023) [Fig. 2]. How peptides work against viruses A diverse microbiota of bacteria, viruses, and eukaryotes resides within the human body. These organisms cooperate with the host’s immune system to perform effective and coordinated activities (Clemente et al. 2012). The viral life cycle comprises five stages: entrance into the host cells, translation, replication, assembly, and exit. Antiviral drug resistance is a substantial clinical challenge, as the development of resistance can be accelerated by selection pressure especially when therapies fail toeffectively suppress viral replication, even if they reduce transmission (Novoa et al. 2005). Antiviral peptides (AVPs) can inhibit viral fusion with host cells by inhibiting viral entry, while others interfere with proteins or enzymes needed for viral replication (Jenssen et al. 2006). AVPs are effective therapeutic options due to their limited adverse effects, high selectivity, and low toxicity, which are influenced by environmental factors, materials, and surface properties (Jabeen et al. 2023). Some AVPs prevent viral fusion by interfering with the conformational changes required for membrane fusion (Düzgüneş et al. 2021a). This mechanism is particularly proomising against enveloped viruses, such as human immunodeficiency viruses (HIV) and coronaviruses, where membrane fusion is crucial (Cosset and Lavillette 2011). Antiviral peptides have also been shown to inhibit the activity of a protein complex known as RNA-dependent RNA polymerases, thereby suppressing viral RNA synthesis to some extent (Zephyr et al. 2021). Additionally, certain viral protease inhibitors that inhibit the cleavage of viral polyproteins into functional units, consequently slowing the production of new viral particles (Mantlo et al. 2020). Peptides as immunomodulators, can modulate immune response by enhancing ability of body to fight against viral infections by stimulating the production of cytokines and hence can boost immune response (Al-Azzam et al., 2020). Some peptides target to prevent viruses using immune-evading techniques, including downregulating major histocompatibility complex molecules or by interfering with interferon responses (Alcami and Koszinowski, 2000). Peptides can provide dual benefit of direct antiviral action and immune system support by enhancing their host immunity, giving them flexible role in antiviral strategies (Solanki et al., 2021). [Fig. 3]. Advantages and challenges of peptides in drug development and physicochemical properties Peptides exhibit high affinity and specificity for their targets, often outperforming small molecules and biologics in disrupting protein–protein interactions (PPIs) due to their smaller size and flexibility (L. Wang. et.al., 2022b). They can be chemically synthesized independently of cellular systems; allowing for easier and more cost-effective manufacturing. This capability also allows the inclusion of specific modifications to enhance their versatility (Rossino et al. 2023). The efficacy and application of peptides in therapeutics are being enhanced by advances in peptide synthesis and delivery technologies, including rational design and phage display (Luo et al. 2023). However, their inherent instability poses challenges in treating chronic conditions where maintaining sustained drug levels is crucial (Rossino et al. 2023). Despite these advantages, therapeutic peptides face several challenges. They typically have poor membrane permeability and in vivo stability, leading to a short half-life and fast in vivo elimination (L. Wang et al., 2022c). The complexity of peptide synthesis and the requirement for strict regulatory compliance can make the development process challenging. [Table 1]. Table 1. | Advantages | Challenges | |---|---| | High specificity | In vivo Stability issues | | Low toxicity | Expensive synthesis | | Easy to modify | Poor bioavailability | | Immunomodulatory properties | Rapid degradation by enzymes | SARS-CoV-2 structure and pathogenesis SARS-CoV-2 is a spherical enveloped virus with a diameter of 65–125 nm and a genome of 30 kb of single-stranded RNA - the largest among known RNA viruses (Ghosh et al., 2022). The virus’s spike protein is a major target for therapy and vaccine design due to its involvement in promoting viral entry into host cells (Singh et al. 2020). The surface of the virus consists of spike proteins, critical to its ability to enter host cells, a process mediated by their interaction with the angiotensin-converting enzyme 2 (ACE2) receptor expressed on human cell surfaces (X. Li et al., 2024a). [Fig. 4] [Fig. 5]. The spike protein is critical for viral entry into host cells and has been a key target in therapeutic and vaccine development (Wu et al., 2022). Structural investigations elucidated the processes through which the spike protein associates with ACE2, highlighting the importance of specific mutations that increase binding affinity and facilitate virus transmissibility (X. Li et al., 2024a). Entry into host cells is initiated by ACE2, causing viral replication, release of new virions that potentially results in cell death and damage to tissue (Wang et al. 2020). The immune response possibly overacts and could lead to complications that include ARDS, failure of multiple organs, and other factors contributing to morbidity and mortality associated with COVID-19 (X. Li et al., 2024a). Several strains of SARS-CoV-2 have emerged and many of them showed increased transmissibility as well as the ability to evade the immune responses (Ghosh et al., 2022). These mutations alter the spike protein structure, either by enhancing its binding to the ACE2 or otherwise to make it evade neutralization by antibodies produced from previous infections or vaccinations (X. Li et al., 2024a). Several potential drug targets have been reported, such as viral proteases and polymerases. These are required for the viral replication process. (Wu et al., 2022). Various vaccine candidates, such as mRNA and inactivated virus vaccines, have been developed, while drugs such as Paxlovid and molnupiravir target these targets. (Ghosh et al., 2022). Vaccines help reduce disease severity and prevent infection by generating robust immunity against spike proteins. Increasingly, there is a need to regulate host immune response, including inflammation and cytokine secretion. (X. Li et al., 2024b). Therapeutic Targets in SARS-CoV-2 Three significant targets of SARS-CoV-2 include spike protein, main protease(Mpro), and RNA-Dependent RNA Polymerase(RdRp). The spike protein facilitates the entry of the virus into host cells and is the target for neutralizing antibodies and vaccines. The high variability presents challenges to the efficacy of vaccines and antibody treatments (Duan et al., 2022). Modern countermeasures can be developed based on monoclonal antibodies and vaccines to efficiently recognize the Spike Protein - even in the context of emerging variants, as well as on the Main protease (Krumm et al., 2021). Main Protease which is regarded as a key protease in the pathogen's replication process (Duan et al., 2022). The specificity of Mpro as a target is beneficial due to its reduced likelihood of having human homologues, potentially minimizing treatment-related side effects (G. Li et al., 2023). RdRp is responsible for synthesizing the viral RNA genome during replication, and inhibitors of this enzyme can effectively impede viral replication, positioning it as a crucial target for antiviral drug development (Zhou et al., 2021). Peptide inhibitors target RdRp regions to reduce off-target effects and block viral replication with broad-spectrum antiviral activity, and stronger binding than nucleotide analogs (Pant and Jena 2021). Remdesivir is an antiviral agent that inhibits RNA-dependent RNA polymerase (RdRp) and may effectively reduce the severity of COVID-19 in certain patients (Krumm et al., 2021). The development of additional RdRp inhibitors has been a focal point in research, as it may offer a strategy for combating the virus during a crucial phase of its life cycle (G. Li et al., 2023). [Table 2]. Table 2. | Target | Function | Therapeutic potential | |---|---|---| | Spike protein (S) | Facilitates viral entry | Inhibits virus binding to ACE2 | | Main protease (Mpro) | Processes viral proteins | Inhibits virus binding to ACE2 | | RNA polymerase (RdRp) | Replicates viral RNA | Blocks viral RNA synthesis | Current approaches to targeting SARS-CoV-2 Monoclonal antibodies can block the ACE-2 receptor, preventing the spike protein of the SARS-CoV-2 virus from binding to host cells. Inhibit TMPRSS2 protease to block viral entry and endosomal fusion (Iacob & Iacob, 2020b). Administering ACE2-targeted antibodies via inhalation by using lipid nanoparticles to precisely target the pulmonary area (Majumder and Minko, 2021a). Monoclonal antibodies and repurposing of remdesivir inhibit viral RNA-dependent RNA polymerase (RdRp) (Iacob and Iacob, 2020b). Combine high-throughput virtual screening with rational drug design techniques to identify novel synthetic and natural product inhibitors that selectively target viral proteases including 3CLpro and PLpro (Gupta et al., 2021). Mitigate the cytokine storm utilizing pharmaceutical agents such as hydroxychloroquine, baricitinib, tocilizumab, and gimsilumab. Administer convalescent plasma containing neutralizing antibodies from recovered patients (Majumder and Minko, 2021b). Complementary and alternative medicine increases innate and adaptive immunity (Gupta et al., 2021). Develop vaccines that target the spike protein of SARS-CoV-2 to provoke neutralizing antibodies. Utilize various vaccine platforms including mRNA, viral vectors, protein subunits, and inactivated virus (Majumder & Minko, 2021b). Peptide-based strategies for SARS-CoV-2 drug discovery Peptides targeting the spike protein Peptide inhibitors can disrupt viral membrane fusion by disrupting envelope protein conformational changes (Düzgüneş et al. 2021b). Stapled hACE2 peptides, for instance, engage the spike protein's receptor binding domain (RBD), potentially blocking viral entry at its initial stage (Maas et al. 2021). Stapled peptides enhance binding affinity, resistance to degradation, and cell permeability, as demonstrated by double-stapled peptides targeting the RSV F protein (Gaillard et al. 2017). Both HIV-1 gp41 and SARS-CoV-2 Spike protein form a six-helix bundle, inhibiting membrane fusion by mimicking HR1-targeting peptides. Additionally, dengue virus envelope-derived peptides inhibit viral infections by binding to the host and preventing the fusion-promoting zipping-up of the E-protein stem (Schmidt et al. 2010). Designed peptide inhibitors such as SARS-CoV-2 PEP 49- which includes amino acidresidues from the α1 helix and β4–β5 sheets of ACE2 - can bind to the ACE2 binding site on spike RBD more tightly than does its natural ligand—the receptor that is encoded by host genes (Khater and Nassar 2022). PEP 49, a 15-amino acid peptide from HIV-1 gp41, inhibits HIV-1 fusion with target cell membranes and shows potential as a SARS-CoV-2 inhibitor. Stapled peptides, in general enhance protease resistance and exhibit improved antiviral activity (Tzotzos 2022). The HR1 domain is among the peptides targeting heptad-repeat (HR) regions of the spike protein, which can form a six-helix bundle that promotes membrane fusion (Ho et al., 2023). Stapled peptides designed to target the HR1 domain have been predicted to block the replication of SARS-CoV-2 (Zheng et al. 2021). A recent study, that the impressive macrocyclic peptide that significantly blocked viral fusion mediated by the spike protein of SARS-CoV-2 (Thijssen et al. 2023). Computational design of peptides can respond to viral mutations by identifying sequences that interact with protein interfaces (Düzgüneş et al. 2021b). Peptide inhibitors for viral proteases A cyclohexyl group at the P2 position and an imidazolyl group at the P1 position have shown effectiveness as inhibitors. Additional interactions through hydrogen bonding receptors should be conducted at the P4 site to facilitate interactions (Zhu et al. 2022). Peptide inhibitors that were developed for the most promising substrate candidates exhibited a high level of selectivity and potent inhibition of both SARS-CoV-1 and SARS-CoV-2 PLpro (Lv et al., 2022). This facilitates inhibitor synthesis and modification against evolving viruses. The main protease (Mpro) and PLpro are key enzymes in SARS-CoV-2 replication. Peptide inhibitors prevent viral propagation by preventing polyprotein processing and modulating the host innate immune response (Narayanan et al. 2022). The substituent groups of existing lead compounds are being reorganized and modified through the application of combinatorial chemistry (Zhu et al. 2022). High-throughput screening and molecular docking techniques to identify inhibitors from small molecule libraries (Zhu et al. 2022). [Fig. 6]. Peptide immunomodulators and vaccines Peptides are a highly effective vaccine antigens due to their specificity, safety, and convenience. Peptides can be designed to target specific epitopes, elicit desired immune responses, or develop effective anti-cancer vaccines for infectious diseases and cancers (Hamley 2022). Particle formulations, delivery optimization, peptide-adjuvant combinations, and combinatorial peptide libraries enhance the immunogenicity of peptide vaccines, leading to improved MHC binding and stability. Immunomodulators, including Toll-like receptors (TLRs), consist of peptides, such as antimicrobial peptides derived from arthropods (Gokhale and Satyanarayanajois 2014a). AI algorithms generate and assess peptide sequences, predict peptide-protein interactions, and bioactivity, toxicity, drug-like properties and analyse datasets to prioritize lead candidates (Gokhale and Satyanarayanajois 2014b). The study on PD-1 blocking peptide delivery demonstrates that viral vectors can improve immune responses to vaccine antigens, lower peptide production costs, and increase CD8 + T-cell responses (Phares et al. 2022). Polymeric nanoparticles (rods, worms, spheres, and tadpoles) deliver peptide antigens and improve stability and immunogenicity. Poly (lactic-co-glycolic acid) (PLGA) nanoparticles encapsulate antigens, prevent degradation, and promote internalization. Additionally, polysaccharides like pullulan, alginate, and chitosan are employed in nanoparticle vaccine preparations (Fujita and Taguchi 2017). Peptide conjugates for SARS-CoV-2 AVPs can bind to either viral proteins, such as the SARS-CoV-2 spike protein, or host cell receptors like ACE2 (Essa et al., 2022a). This binding can inhibit virus attachment and entry into host cells (Schutz et al., 2020). AVPs have broad-spectrum therapeutic potential against many viruses, not just coronaviruses (Mahendran et al. 2020). For instance, hardly any peptides exhibit efficacy against HIV, influenza, and other respiratory viruses (Schutz et al., 2020). As a result, dendrimer-peptide conjugates hold potential for therapy due to enhanced binding affinity and specificity of AVPs and successful inhibition of interaction between the SARS-CoV-2 spike protein and ACE2 (Jeong et al. 2023). The other strength of the present study is that we identified the peptides whose properties are already known, thus, facilitating the discovery of new antiviral drugs (Blanas et al. 2022). This is particularly important in the context of highly infectious viral diseases such as SARS-CoV-2, because time becomes critical factor (Mahendran et al. 2020). Many peptides have already passed preliminary safety tests in various contexts, which has expedited the approval process for new applications. In the acute need for highly effective COVID-19 treatments, this is very crucial (Schutz et al., 2020). Insights gathered from earlier research on peptide interactions with viral proteins may influence the creation of novel peptides specifically targeting SARS-CoV-2 (Essa et al., 2022a). Known peptides used as therapeutics against viral diseases—antiviral Antiviral peptides constitute a promising category of therapeutics aimed at addressing viral infections. These peptides target multiple stages of the viral life cycle, encompassing viral attachment, penetration, and replication (Lee et al. 2022). Their mechanisms of action typically involve disrupting viral membranes, inhibiting cellular entry, and interfering with viral genome replication (Vilas Boas et al. 2019). Examples of antiviral peptides Enfuvirtide (T-20): This represents the inaugural FDA-approved peptide drug utilized as a fusion inhibitor in HIV treatment. Demonstrated broad-spectrum efficacy against coronaviruses, offering protection against infections in transgenic mouse models (Y. Liu et al. 2023). EKL1C: Demonstrated broad-spectrum efficacy against coronaviruses, offering protection against infections in transgenic mouse models (Y. Liu et al. 2023). Cyclotides: These peptides exhibit antiviral properties by disturbing the lipid envelope of viruses, which is crucial for their ability to infect host cells (Y. Liu et al. 2023). Aclerastide: A peptide used for treating diabetic foot, diabetic foot ulcers, and foot ulcers. Approved in the early 2000s, it enhances wound healing by promoting angiogenesis and cellular repair (Drugs | FDA, n.d.). Leuprolide: A peptide used to treat prostate cancer and hormone-related conditions. Approved in 1985, it agonizes GnRH receptors to modulate hormone release, reducing sex hormone levels(Drugs | FDA, n.d.). Follitropinbeta: A peptide that treats infertility by stimulating ovarian follicle growth. Approved in 1997, it stimulates ovarian and testicular function by mimicking FSH(Drugs | FDA, n.d.). GramicidinD: A peptide used as an antibiotic for topical infections. Approved in 1993, it disrupts bacterial membranes by forming ion channels, causing cell death(Drugs | FDA, n.d.). Bivalirudin: A peptide used as an anticoagulant during coronary angioplasty. Approved in 2000, it inhibits thrombin to prevent clot formation (Drugs | FDA, n.d.). Secretin: A peptide hormone used to treat acute heart failure and diagnose growth hormone deficiency. It helps in maintaining body fluid homeostasis and modulates the secretion of bile, pancreatic bicarbonate, and gastric acid (Drugs | FDA, n.d.). Cenderitide: A natriuretic peptide used for treating acute decompensated heart failure (investigational use). Approved in 2012, it agonizes natriuretic peptide receptors to induce vasodilation and diuresis (Drugs | FDA, n.d.). Thymalfasin: Peptide used as an immune modulator in various conditions. Approved in the 1980s, it enhances T-cell function and immune responses (Drugs | FDA, n.d.). Nesiritide: Nesiritide used to treat acute heart failure. Approved in 2001, it activates natriuretic peptide receptor s to promote vasodilation and diuresis (Drugs | FDA, n.d.). Lenomorelin: A synthetic peptide used to diagnose growth hormone deficiency. Approved in the early 2000s, it mimics ghrelin to stimulate appetite and growth hormone release (Drugs | FDA, n.d.). Glucagon recombinant: A peptide used to treat severe hypoglycaemia. Approved in 1998, it raises blood glucose levels by stimulating glycogen breakdown (Drugs | FDA, n.d.). Mecasermin: A peptide used to treat growth failure in children with severe primary IGF-1 deficiency. Approved in 2005, it stimulates growth by mimicking insulin-like growth factor-1 (IGF-1)(Drugs | FDA, n.d.). Cosyntropin: A peptide used to diagnose adrenal insufficiency. Approved in 1970, it stimulates cortisol production by mimicking ACTH(Drugs | FDA, n.d.). Liraglutide: Peptide treats type 2 diabetes and obesity. Approved in 2010, it activates GLP-1 receptors to enhance insulin release and reduce appetite(Drugs | FDA, n.d.). Insulin aspart: Used to manage blood sugar levels in diabetes mellitus. Approved in 2000, it lowers blood glucose by facilitating glucose uptake into cells (Drugs | FDA, n.d.). Thymosin beta-4: Peptide used for tissue repair and regeneration. Approved in the early 1980s, it promotes tissue repair and cell migration(Drugs | FDA, n.d.). Benefits of peptide repurposing The drug development process can be significantly enhanced through peptide repurposing, which includes the utilization of existing peptide drugs for novel therapeutic targets or indications. The significance of this approach becomes particularly valuable in the context of emerging viral diseases, where rapid actions are important (Egieyeh et al. 2021). Utilization of peptides that have already been approved enables the completion of clinical trials and regulatory approval procedures more rapidly, as their safety profiles are well-established (Chaurasiya et al. 2023). The cost of research and development can be reduced by repurposing of existing drugs, as compared to the development of novel compounds from scratch (Egieyeh et al. 2021). Number of initially emerged peptides to treat one disease may be effective against several diseases, which makes them useful for treating infectious diseases or recently discovered viruses (Chowdhury et al. 2020). Recent research has shown that some FDA-approved peptides may effectively combat COVID-19 and other viral infections by targeting interactions between the virus and host cells (Egieyeh et al. 2021). In addition to expanding treatment options, this also fulfills the immediate demand for strong antiviral drugs in the context of increasing resistance to drugs. Recent advances and innovations in peptide synthesis and design Peptide engineering: cyclization, stapling, and stabilization Peptides are making significant strides as therapeutic agents; however, researchers have developed several ways to combat their inherent limitations (Barman et al. 2023). One of these methods is through structural modifications such as cyclization, stapling, and stabilization which aims to enhance the functional properties and effectiveness of peptide-based therapeutics (Musaimi et al. 2022). Lengthy bioactive peptides can now be structurally fortified through hydrocarbon double-stapling technique that can also help in solving their proteolytic vulnerability (Bird et al. 2010). It is becoming more widely recognized that adding an all-hydrocarbon “staple” within short peptide sequences might improve the peptides’ stability, protease resistance, cell penetrance, and targeted bioactivity (Walensky and Bird 2014). Apart from stapling, various peptide engineering techniques including modifications on the backbone and side-chains, amino acid substitutions and computational approaches among others have been on the rise (Klein 2017). These modifications have helped in enhancing certain functionalities of peptides such as their proteolytic stability, ability to penetrate membranes and specificity to certain targets (Nevola and Giralt 2015) (Barman et al. 2023). The latest developments in stapling methods usually involve the incorporation of non-natural amino acids into their structure and use of different types of chemical cross-linkers during their synthesis (Arbour et al. 2020). Stabilization strategies improve pharmacokinetic properties, such as enhanced membrane permeation and increased resistance to proteolytic degradation, by incorporating non-natural aminoacids, among other methods (Masui and Fuse 2022). Cyclization forms a circular structure, improving metabolic stability, binding affinity, and membrane permeability (Vu et al. 2021). Hydrocarbon stapling and fluorine thiol displacement reactions stabilize peptides, enhancing resistance to proteolytic degradation (M. S. Islam et al., 2022a). Peptide drugs like Liraglutide and Semaglutide have a real-world impact in cancer therapy, obesity, and osteoarthritis (Ferková et al. 2023), (Zhan et al. 2024). Additionally, microflow synthesis technology produces more stable peptide variants, resulting in higher purity levels and improved volumes through precise control of reaction conditions (Fuse et al. 2018). Peptide synthesis has been transformed by the integration of automated synthesis platforms and new coupling chemistries. Automated synthetic sites can rapidly create complex peptide chains, even those with a lot of modifications (Charalampidou et al. 2024). [Table 3]. Table 3. | Innovation | Description | Impact | |---|---|---| | Peptide cyclization | Creating cyclic peptides for stability | Improved bioavailability | | Peptide stapling | Adding chemical staples to increase rigidity | Increased potency and stability | | AI-based Peptide Design | Using machine learning to predict peptide structure | Accelerates drug development | Computational tools for peptide design Drug discovery relies immensely on computational modelling that helps in identifying highly binding molecules for protein receptors (Chang et al. 2022). Among the important aspects are small molecule virtual libraries, docking software efficiency and physics-based approaches (Chodera et al. 2011). Nonetheless, there are some limitations such as multiple binding modes, receptor plasticity, large conformational changes, highly charged systems and between pairs of compounds comparisons. To bind, most small molecule drugs usually need a receptor protein pocket where they fit well (Liang et al. 1998). On the other hand, peptide is a more flexible type of molecule that binds more specifically to receptors even without pockets; thus, once considered undruggable by small drugs molecules (Balliu and Baltzer 2017). The truth is our cells already use them as signalling molecules (Cunha et al. 2008) while many protein–protein interactions happen through peptide epitopes (Wai et al. 2018). Additionally, compared with big biological compounds, peptides can also be designed to possess properties that enable them to cross cell membranes easily enough (Xie et al. 2020). In this approach, drugs are developed faster; they are cost effective in terms of both time and money. The most promising molecules are therefore selected for further research using virtual screening and molecular docking techniques (Stanzione et al. 2021). So far, the ‘educated guesses’ generated have led to several lead compounds,including drugs such as imatinib (Kuntz et al. 1982), zanamivir (Rarey et al. 1996), nelfinavir (Jones et al. 1997), erdafitinib (Mark & van Gunsteren 1994), which is used to treat leukemia and breast cancer.Additionally, some clinical candidates took advantage of computer methods during their discovery or optimization processes (Thomas and Dill 1996). Molecular docking, a structure-based approach to predict peptide binding to target proteins, was developed in the 1980s and is widely used. It simulates protein–protein interactions, generates binding conformations and scores them to select the most likely modes (Patrick Walters et al. 1998). When there is an available three-dimensional (3D) structure of a protein target, it is the preferred method for discovering new drugs. The rise in molecular docking’s popularity was fueled by increased computational resources and the greater accessibility to small-molecule and protein structures during the last two decades (Biswas et al. 2022). Virtual screening searches compound libraries, including peptides, for drug candidates (Porto 2021). Deep learning is particularly well suited for peptide drug discovery, including sequence generation, structure prediction and binding affinity (S. Chen et al. 2024). Machine learning improves peptide drug design by predicting stability, improving target binding, and predicting binding sites on proteins (Yin et al. 2024). AlphaFold and Rosetta contribute to peptide drug discovery by providing accurate structural information and rational design (S. Chen et al. 2024). The objective of protein research has been to produce intelligent devices that can mimic human behaviour. Methods for predicting the secondary structures of proteins using machine learning were developed in 1992, and these developments moved the study of proteins and their structure forward (Greener et al. 2019). Machine learning involves algorithms that can analyse and learn from the data and then predict the future state of any new data sets (Vamathevan et al. 2019). It is based on datasets of peptides generated through high-throughput sequencing and computational methods that predict highly accurate functional peptides (Basith et al., 2020a). Strong machine-learning algorithms for peptide data processing include support vector machines, random forests, and deep learning. These methods increase accuracy and the effective capture of biological complexity and activity (Basith et al., 2020b). ML models offer a comprehensive understanding of behavior and interaction, provide information on peptide properties, and use techniques such as Pseudo Amino Acid Composition (PSEAAC) that allow for more accurate predictions (Y. Wang et al. 2023a, b). Challenges and solutions in peptide drug development for SARS-CoV-2 Overcoming stability and bioavailability issues Peptide therapeutics suffer from stability and bioavailability issues due to enzymatic degradation in the gastrointestinal tract and bloodstream (Lau et al., 2015). Strategies to improve bioavailability include peptide stapling, cyclization, fluorine-thiol displacement, chemical modifications, and lipid-based nanocarriers (L. Wang et al., 2022d). Other approaches, such as peptide stapling and cyclization, fluorine thiol displacement reactions, chemical modifications, and newer delivery methods like lipid-based nanocarriers have also been reported for improvement peptide bioavailability (M. S. Islam et al., 2022b). These methods protect peptides from the proteolytic activity and improve permeation across the intestinal border, making them suitable for increasing the oral bioavailability of therapeutic peptides (Naim et al. 2022). One of the biggest challenges of peptide drugs is their poor ADME properties (Madhavan et al., 2021a). This may be since peptides are easily degraded in the body and therefore not effective as therapeutic agents (Essa et al., 2022b). Furthermore, binding peptides to specific virus proteins such as SARS-CoV-2 spike protein will prevent the virion from entering the host cell (Madhavan et al., 2021a). Designing peptides that effectively bind to these sites and remain stable is not an easy task (Essa et al., 2022b). The rapid mutation of SARS-CoV-2 has given rise to new variants which can change how effective previous peptide therapeutics were based on earlier strains. Hence constant research and updating of peptide designs is required (Essa et al., 2022b). It often takes a long time for peptide drugs to get regulatory approval as they require numerous clinical trials demonstrating their safety and efficacy which delays their availability in urgent situations (Madhavan et al., 2021a). Encapsulation of peptides in nanoparticles, lipids attached to peptides and polyethylene glycol groups are also used for improving stability, resistance to proteolytic degradation and cellular uptake (Nissan et al. 2024). Peptide delivery involves various types of nanoparticles such as liposomes, polymeric nanoparticles, solid lipid nanoparticles and inorganic nanoparticles (Chatterjee and Sivashanmugam 2024). These nanoparticles enhance bioavailability, targeted delivery, pH-responsive release, and intracellular delivery of therapeutic peptides (H. Liu et al., 2024). Nanocarriers such as polyarginine nano capsules and polymeric hydrogels improve peptide drug therapeutic index by protecting them from degradation, enhancing permeation and facilitating controlled release (Atabakhshi-Kashi et al., 2020). The new methods in computational biology have made it possible to use in silico techniques for the design of peptides that can interact well with viral proteins (Moroy and Tuffery 2022a). This enables the fast screening and optimization of potential peptide candidates before their synthesis and testing (Madhavan et al., 2021a). According to research findings, there are key interactions that exist between SARS-CoV-2 spike protein and Human Angiotensin Converting Enzyme 2 (ACE2). By using antiviral peptides already known to be effective against related viruses, the process of creating new ones can be shortened (Madhavan et al., 2021a). To enhance bioavailability issues, scientists are looking into nano formulations that improve stability as well as delivery of peptide therapeutics (Essa et al., 2022b). AI algorithms can generate and assess peptide sequences, predict peptide–protein interactions, and predict bioactivity, toxicity, and drug-like properties. This will lead to more effective antiviral peptide therapeutics against SARS-CoV-2 and variants (Goles et al., 2024). Vaccine production targets cost reduction, supply chain optimization, and decentralized manufacturing. mRNA vaccines require less capital but have a higher total cost per dose (Hamidi et al., 2021). These technologies improve pharmacokinetics for peptides making them more useful in therapeutic management (Rossino et al., 2023). Delivery systems for peptide drugs In the early 1900s, Paul Ehrlich introduced the notion of targeted drug delivery. To deliver small molecule drugs (less than 500 Da) and therapeutic proteins, peptide-drug conjugates, injectable biodegradable particles, and depots are used as peptide-based drug delivery systems (Berillo et al., 2021a). Compared to synthetic systems, the peptide-based DDSs have several advantages concerning better biocompatibility and biochemical and biophysical properties, nontoxicity, controlled molecular weight via solid-phase synthesis, and purification (Berillo et al., 2021b). Certain peptides can enter the cell without disrupting the integrity of the cellular membrane and might be considered effective and safe DDSs. Such a group of peptides are generally categorized as cell-penetrating peptides (D. Zhang et al., 2016) First, CPPs were derived from the α-helical domain of the TAT protein encoded by the human immunodeficiency virus type 1—HIV1—and covered the residues from 48 to 60 (Tesauro et al., 2019). Different types of peptides like cyclic, linear, amphiphilic, and α-helical/β-sheet can self-assemble into a variety of nanostructures such as nanotubes, fibers, spheres, and vesicles (Tesauro et al., 2019). This has led to a lot of material diversity through efforts in exploring the self-assembly processes of linear peptides and individual amino acids across several disciplines (Diaferia et al., 2018a, b). A recent study proposes a Gd-DTPA and Gd-DOTA functionalized polymer-peptide for MRI imaging applications (Diaferia, Balasco, Sibillano, Ghosh, et al., 2018). Peptides and proteins move across membranes primarily through transcellular or paracellular routes (Yu et al., 1996). Since proteins and peptides are electrically charged molecules, their move through the plasma membrane is hindered by its lipophilic nature as a result paracellular transport occurs predominantly. Large molecular sizes encounter more resistance (Barbour and Lipper 2008). To achieve amplified therapeutic impacts while reducing healthy tissue damage, peptides can be designed to specifically hone in on certain cells or organs (Lian and Ji 2020). Peptides could also improve drug pharmacokinetics and enhance its entry into tumors (L. Wang et al., 2022c). Moreover, peptide carriers may deliver larger biologics like proteins along with smaller drug molecules (Berillo et al., 2021a). This type of delivery would be particularly applicable where drugs have low bioavailability if taken systemically (Mahto et al., 2023). Blood–brain barriers could be utilized for drug-delivery purposes active against neurological diseases by peptides. Plasma peptides are degraded by enzymes; therefore, developing strategies to increase access is of paramount importance for wide applications (L. Wang et al., 2022c). Case studies and ongoing clinical trials of peptide drugs for COVID-19 Currently under development peptide-based drugs Some peptides which can elicit a strong immune response have been identified. For example, it has been shown that the RBD 484–508 peptide produces neutralizing antibodies against SARS-CoV-2 and greatly improves T-cell immunity (Murdocca et al., 2023). In addition, extensive research is ongoing to determine how to use multi-epitope vaccines that incorporate multiple conserved peptides to amplify and broaden immune response to variations of SARS-CoV-2 (Magazine et al., 2023). Currently available vaccines are predominantly induce antibody response that may wane over time. Peptide-based vaccines, on the contrary, offer promise in the improvement of T-cell responses that are very crucial to immunity and probably acts as a line of defence in case antibody levels fall. The development of new, more effective strategies for vaccination will only be possible if personalized peptide-based vaccines are designed according to the immune profile of each patient, especially in key populations such as the elderly and other immunocompromised individuals (Murdocca et al. 2023). Antimicrobial peptides (AMPs) modulate the immune system through direct antimicrobial activity and affect innate and adaptive responses. Their immunomodulation varies according to environmental stimuli, cells, receptor interactions, signalling pathways and transcription factors (Duarte-Mata and Salinas-Carmona 2023). Innate immune system: The body’s first line of defence, responding to germs and foreign materials with host defence and muramyl peptides. Adaptive immunity: Unlike innate immunity, recognizes self from non-self through T cell antigen receptor recognition, co-stimulation from APCs, cytokine environment and MADS recognition (Tang et al. 2024). Other peptides in immune modulation Search results: IDR-1 activates signalling pathways, chemokines, and anti-inflammatory mediators, improving monocyte recruitment and inflammation control (Flemming 2007). Peptides in vaccines modulate innate immunity to minimize adverse reactions and increase efficiency. Low immunogenicity can be overcome with TLR agonists and adjuvants (Tang et al. 2024). Peptides and peptidomimetics can activate immune responses, promote disease tolerance, and understanding B- and T-cell epitopes is crucial for effective therapies (Gokhale & Satyanarayanajois, 2014c). Targeting conserved spike protein regions ensures effectiveness against mutations, and peptides are active against SARS-CoV and MERS-CoV (Yurina 2020). Traditional vaccines are longer to prepare in comparison with peptide-based platforms, which can be prepared in a record time and thus allow quick response against emerging strains or newly discovered pathogens (Gao et al. 2021). The immunomodulatory peptides RKDVY, EW, KE, and AEDG, maintain the normal cytokine production along with the anti-inflammatory activity. They regulate inflammation by the balance of pro-inflammatory and anti-inflammatory cytokines (Simon 2011). They also influence CD4 + T-cell activating and suppression through costimulatory pathways (Gokhale & Satyanarayanajois, 2014d). Peptides bind to major histocompatibility complex molecules, and influence antigen presentation and innate immunity through lipopolysaccharide binding or PAMP interactions (Tang et al. 2024). Peptides can regulate immune responses a lot, so they are useful in preventing complications like acute respiratory distress syndrome (ARDS) and multiple organ failure. Antiviral peptides are similarly being developed to block SARS-CoV-2 entry into host cells (Bagwe et al., 2022a). Targeting conserved regions of viral proteins (for example, in the S, N, and M proteins of SARS-CoV-2) is an effective vaccine strategy with reduced immune escape (Patel and Agrawal 2023). These regions are highly conserved across variants and related coronaviruses and thus less susceptible to mutation. Some peptides from conserved SARS-CoV-2 regions are shown to show potential cross-reactivity with other coronaviruses, suggesting that vaccines targeting these conserved epitopes can protect against different variants (C. Y. Wang et al., 2023a, b). Combining several conserved peptides offers enhanced immune protection, with wide immune response, enhanced population coverage, reduced immune escape and cross-protection (Dey et al., 2023). Trials of peptide vaccines have shown promising immune responses and clinical outcomes (Yoshitake et al., 2015). Combination peptide vaccinations have improved overall survival in patients with advanced cancer. Multi-epitope vaccine approaches provide precise and cost-effective protection against variants (Sarvmeili et al., 2024). Personalized peptide vaccination (PPV) strategies show potential benefits for high-risk groups, with a median overall survival of 7.9 months in patients with advanced bladder cancers (Sasada et al., 2012). Peptide medications that have been successful against SARS-CoV before are being repurposed for COVID-19 treatment with the hope that it will drive the development of effective therapies from what we already know (Madhavan et al., 2021b). Clinical trials are evaluating COVID-19 therapies based on peptides to assess their safety and effectiveness while also identifying potential future candidates for public approval (Bagwe et al., 2022a). The flexibility of peptide medicines, such as their ease of synthesis and modification, puts them in a good position in an ongoing battle against COVID-19 (Moroy and Tuffery 2022b). [Table 4]. Table 4. | Name | Length | Company | Year | Sequence | Type | Mechanism of action | Disease | |---|---|---|---|---|---|---|---| | Corticorelin | 41aa | Ferring Pharm | 1996 | SEEPPISLDLTFHLLREVLEMARAEQLAQQAHSNRKLMEII | Adrenocorticotropic hormone (ACTH) and its derivatives | Stimulant | Cushing’s | | Cosyntropin | 24aa | Celtic Pharma | 2008 | SYSMEHFRWGKPVGKKRRPVKVYP | Stimulant | Adrenal Insufficiency | | | Seractide | 39aa | Armour Pharm | 1905 | SYSMEHFRWGKPVGKKRRPVKVYPNGAEDESAEAFPLEF | Stimulant | Adrenal Insufficiency | | | Ceruletide | 10aa | Pharmacia and Upjohn, Farmitalia Carlo Erba | 2000 | XQDXTGWMDF | Cholecystokinin analogs | Secretagogue | Pancreatitis | | Taltirelin | 2aa | Tanabe Seiyaku | 2005 | HP | Agonist | Hypothyroidism | | | Protirelin | 3aa | Abbott, Ferring Pharms | 1976 | GHP | Thyroid Stimulating Hormone Releasing Hormone | Releasing Hormone | Thyroid Function Test | | Sermorelin | 30aa | Serono Labs, | 1997 | YADAIFTNSYRKVLGQLSARKLLQDIMSRQ | Agonist | Growth Hormone Deficiency | | | Kabi, Pharmacia | Stimulant | Growth Hormone Deficiency | ||||| | Ferring Pharm | Releasing Hormone | Lipodystrophy | ||||| | Somatorelin | 44aa | Thera technologies | 1989 | YADAIFTNSYRKVLGQLSARKLLQDIMSRQQGESNQERGARARL | Growth hormone releasing hormone (GHRH) and analogs | Secretagogue | Pancreatic Disorders | | Tesamorelin | 44aa | ChiRho Clin | 2010 | YADAIFTNSYRKVLGQLSARKLLQDIMSRQQGESNQERGARARL | Secretagogue | Pancreatic Disorders | | | Secretin (human) | 27aa | ChiRhoClin | 2004 | HSDGTFTSELSRLREGARLQRLLQGLV | Immunomodulator | Hepatitis B | | | Secretin (porcine) | 27aa | SciClone Pharms International | 2006 | HSDGTFTSELSRLRDSARLQRLLQGLV | Secretin | Immunomodulator | Immunodeficiency | | Thymalfasin | 28aa | Recordari, Italofarmaco, Johnson&Johnson | 2001 | SDAAVDTSSEITTKDLKEKKEVVEEAEN | Inhibitor | Osteoporosis | | | Thymopentin | 5aa | AstraZeneca,GNR Pharma,Lafon,Lisapharma,Pharmy II,Sandoz-NovartisPharma,Sanofi-Aventis,TRBPharma,Zambon France | 2021 | RKDVY | Thymus hormone | Inhibitor | Osteoporosis | | Salmon Calcitonin | 32aa | Gelacs Innovation | 1986 | CSNLSTCVLGKLSQELHKLQTYPRTNTGSGTP | Inhibitor | Hypercalcemia | | | Elcatonin | 31aa | Novartis Pharma | 2021 | SNLSXXVLGKLSQELHKLQXYPRXDVGAGXP | Calcitonin | Stimulant | Osteoporosis | | Human Calcitonin | 32aa | Eli Lilly | 1989 | CGNLSTCMLGTYTQDFNKFHTFPQTAIGVGAP | Antagonist | Preterm Labor | | | Teriparatide | 34aa | Ferring Pharms | 2002 | SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF | Agonist | Postpartum Hemorrhage | | | Atosiban | 9aa | Ferring Pharms | 2000 | XYITNCPXG | Parathyroid hormone derivatives | Agonist | Labor Induction | | Carbetocin | 8aa | Abbott, APP Pharms, Baxter Healthcare, JHP Pharms, King Pharmas, Novartis Pharma, Teva | 1997 | YSPRLEGL | Oxytocin analogs and antagonists | Agonist | Prostate Cancer | | Oxytocin | 9aa | Sanofi-Aventis | 1953 | CYIQNCPLG | Agonist | Infertility | | | Buserelin | 9aa | Baxter Healthcare, Ferring Pharms, Sanofi-Aventis, Wyeth Pharms | 1984 | EARGPRHET | Agonist | Prostate Cancer | | | Gonadorelin | 10aa | AstraZeneca | 1979 | PYRHISTRPS | Gonadotropin-releasing hormone (GnRH) and analogues | Agonist | Prostate Cancer | | Histrelin | 9aa | Abbott, Alza, AstellasPharma, Bayer, Bedford Labs, Genzyme, Johnson&Johnson, QLT, Sanofi-Aventis, Takeda,Teva, Wyeth | 1991 | XHWSYXLRP | Agonist | Endometriosis | | | Leuprolide | 9aa | Pfizer, Searle | 1985 | XHWSYLLRP | Agonist | Prostate Cancer | | | Nafarelin | 10aa | Debiopharm, Ferring Pharms, Beaufour Ipsen Pharma, Watson Labs | 1990 | EARGPRGLY | Antagonist | Prostate Cancer | | | Triptorelin | 10aa | Praecis Pharms, Speciality European Pharma | 2000 | XHWSYWLRPG | Antagonist | Infertility | | | Abarelix | 10aa | AEterna Zentaris, Merck-Serono | 2003 | XXXSYNLXPA | Antagonist | Prostate Cancer | | | Cetrorelix | 10aa | Ferring Pharms, Astellas Pharma | 2000 | PYRHISTRPS | Antagonist | Infertility | | | Degarelix | 36aa | Organon | 2008 | YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF | Gonadotropin releasing hormone (GnRH) antagonist | Diagnostic | Lung cancer | | Ganirelix | 10aa | Amersham Health, Berlex Labs, CIS bio Intenational, Nycomed Imaging | 1999 | XXXSYXLXPA | Diagnostic | Neuroendocrine Tumors | | | Depreotide | 10aa | Molecular Insight Pharms | 1999 | THRCYSTHRL | Inhibitor | Acromegaly | | | Edotreotide | 7aa | Beaufour Ipsen Pharma, Globopharm, Tercica | 2008 | DPHECYS | Inhibitor | Acromegaly | | | Lanreotide | 9aa | Abraxis Pharma, Bedford Labs, Sandoz-Novartis Pharma, Teva | 2007 | LCYSTHRNH | Somatostatin analogs and antagonists | Diagnostic | Neuroendocrine Tumors | | Octreotide | 8aa | Mallinckrodt, Bristol-Myers Squibb | 1988 | FCFWKTCT | Inhibitor | Gastrointestinal Bleeding | | | Pentetreotide | 8aa | Merck-Serono | 1994 | STHRCYST | Inhibitor | Esophageal Varices | | | Somatostatin | 14aa | Debiopharm, H3 Pharma | 1978 | HAGCKNFFWKTFC-OH | Agonist | Diabetes Insipidus | | | Vapreotide | 8aa | Monasrch/King Pharms | 1988 | FCYWKVCW | Agonist | Esophageal Varices | | | Argipressin | 9aa | Apotex, Bausch & Lomb Pharms, Barr Labs, Behring, Ferring Pharms, Hospira, Pharmaceutique Noroit, Sanofi-Aventis, Teva | 1960 | CYFQNCPRG | Inhibitor | HIV | | | Terlipressin | 12aa | Roche | 2022 | GGGCYFQNCPKG | Immunomodulator | Multiple Sclerosis | | | Enfuvirtide | 36aa | Teva | 2003 | YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF | Vasopressin analogs | Blocker | Chronic Pain | | Glatiramer | 4aa | Elan Pharms | 1996 | EAYK | Antagonist | Hypertension | | | Ziconotide | 25aa | Norwich-Eaton Pharms, Procter & Gamble | 2004 | CKGKGAKCSRLMYDCCTGSCRSGKC | Inhibitor | Thrombosis | | | Saralasin | 8aa | Nycomed Pharma, The Medicines Company | 1970 | SRVYVHPA | Agonist | Heart Failure | | | Bivalirudin | 20aa | Millennium Pharms, GSK, Schering-Plough | 2000 | PPRPGGGGNGDFEEIPEEYL | Antagonist | Angioedema | | | Nesiritide | 32aa | Jerini AG | 2001 | SPKMVQGSGCFGRKMDRISSSSGLGCKVLRRH | Anti-HIV drugs | Agonist | Diabetes | | Icatibant | 10aa | Amylin Pharms, Eli Lilly | 2011 | RRXPXGXSXR | Central Nervous System | Agonist | Diabetes | | Exenatide | 39aa | Novo Nordisk | 2005 | HGEGXFXSDLSKQMEEEAVRLFXEWLKNGGPSSGAPPPS | Peripheral nervous system | Agonist | Diabetes | | Liraglutide | 31aa | Sanofi-Aventis | 2010 | HAEGTFTSDVSSYLGGQAAKEFIAWLVRGRG | Cardiovascular | Agonist | Diabetes | | Lixisenatide | 44aa | GSK | 2016 | HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK | Agonist | Diabetes | | | Albiglutide | 30aa | Eli Lilly | 2014 | HGEGTFTSDVSSYLEGQAAKEFIAWLVKGR | Analog | Diabetes | | | Dulaglutide | 46aa | Amylin Pharms | 2014 | CAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGEYKFQNA | Surfactant | Respiratory Distress Syndrome | | | Pramlintide | 37aa | Ironwood Pharmaceuticals/Forest Laboratories, Almirall | 2005 | LYSCYSASNTHRALATHRCYSALATHRGLNARGLEAL | Agonist | Short Bowel Syndrome | | | Sinaspultide | 21aa | Novartis | 2007 | KLLLLKLLLLKLLLLKLLLLK | Angiotensin | Agonist | Diagnostic | | Teduglutide | 33aa | Affymax, takeda | 2012 | CYCLRAMINETHYLCARAMYLYLPFWKENYLYF | Others | Vasodilator | Pulmonary Hypertension | | Pentagastrin | 5aa | Senatalk | 1973 | AWMDF | Vasodilator | Gastric carcinoma | | | Aviptadil | 28aa | Cambridge Labs, SERB Labs, Wyeth-Ayerst Labs | 2020 | HSDAVFTDNYTRLRKQMAVKKYLNSILN | Vasodilator | Acute respiratory distress syndrome (ARDS) | Peptide therapeutics for respiratory viruses Cell-penetrating peptides in antiviral peptide-drug conjugates offer several advantages in delivery of the antiviral agents active against respiratory viruses such as RSV and coronaviruses (Todorovski et al. 2023). A new platform of stapled lipopeptides targeted conserved viral proteins for a broad-spectrum antiviral strategy (Bird et al. 2024). Intranasal treatment has been shown to significantly preventnasal infections and importantly reduced viral spread. Also, peptides such as thymalin and immunomodulatory sequences exert cytokine-balancing activity in individuals with COVID-19 and thus are likely to prevent inflammatory reactions, enabling therapy for ARDS by modulating the cytokine storm (Khavinson et al., 2020a). Different improvements, such as SPPS in peptide synthesis, enable the mass production of therapeutic peptides. This enhances the pharmacokinetic profile, therefore improving the self-assembly peptide systems that are capable of effectively accomplishing drug delivery to target tissues (Moroy and Tuffery 2022b). Application of some peptides, such as thymalin and immunomodulatory sequences, has gained a certain enthusiasm because of their potential to restore cytokine homeostasis and prevent acute disproportionate inflammatory responses in COVID-19 patients. The peptides modulate immune responses and may have a role in the management of the cytokine storm associated with acute respiratory distress syndrome in severe cases of COVID-19 (Monroe et al., 2022a). Entry inhibitor peptides target the viral entry steps, including receptor binding, protease processing, endocytosis, or fusion, against respiratory viruses such as SARS-CoV-2 and IAV (Behzadipour and Hemmati, 2022a). Stapled have been demonstrated for the potential prevention and treatment of the infections of SARS-CoV-2. These peptides target the highly conserved HR2 domain of the viral spike protein to inhibit viral entry (Zhao et al., 2020). Entry inhibitor peptides like AntiSCV2P1 and AntiSCV2P7 are also being developed that target the viral fusion protein to prevent infection (Behzadipour and Hemmati, 2022b). Peptide-based fusion inhibitors targeting influenza HA are being pursued as an alternative to small-molecule antivirals, especially for RSV infections in infants and the elderly (Nyanguile 2019). Use of peptides in making antiviral-peptide-linker-drug conjugates through cell-penetrating peptides has shown much promise in augmenting the delivery of antiviral agents against RSV (Zhao et al., 2020). The ability of peptides to specifically target conserved viral proteins and modulate immune responses and to be components for developing drug delivery systems makes them attractive candidates for designing broad-spectrum antivirals against respiratory viruses (Monroe et al., 2022b). Ongoing research is directed at improving their stability, pharmacological properties, and scalable production to advance peptide therapeutics into clinics (Sharma et al., 2023). Challenges from ongoing clinical trials Patient recruitment is a challenge for 55% of those surveyed and is increasing the duration of clinical trials, heightening the complexity gripping due to COVID-19. Most of the patients are not aware of the enrolment of patients into the clinical trials; hence, it is difficult to find study centers as it is a cooperation between different stakeholders like sponsors, investigators, patients, payers, physicians, and regulators (Institute of Medicine (US) Forum on Drug Discovery, 2010). Patient enrolment and retention are disrupted due to various issues such as inaccessibility of patients, travel restrictions, and COVID-19 care prioritization (Margas et al., 2022). Since the pandemic is still ongoing, it caused operational gaps and delays in trials; therefore, monitoring, data collection, and following a protocol carefully is a matter of prime importance (Sathian et al., 2020). Staff shortages, the delay in the opening of the sites, and challenges of the pandemic make UK trials suffer in accordance, as 18% fewer commercial trials started compared to 2019 (Lorenc et al., 2023). Some of the challenges faced by trials include those on elective procedures, virtual and decentralized approaches, resourcing, and protocol changes. Early on, there were fewer initial disruptions in Asia (Upadhaya et al., 2020). One prevalent alteration that has occurred is the prioritizing of studies connected to COVID-19. In response to the virus, organizations like the National Institutes of Health have reallocated millions of dollars to support research aimed at better understanding and combating the virus (Narahari et al., 2024) As a matter of fact, the NIH spent more than $4 billion in COVID-19 research, and this money included the cost for diagnostics, therapeutics, and vaccine development. This has quickly been mobilized to advance large consortiums and clinical trials, reflecting an unprecedented response to a public health crisis (Angelis et al., 2022). Besides prioritizing COVID-19 studies, funding agencies have taken measures that make sure non-COVID-19 research is continued (Walker et al., 2021). The pandemic urges agencies to give priority to ongoing research in chronic diseases, cancer, and drug development with a view to balancing immediate public health needs with long-term research agendas (Miller and Williams 2022). Funding agencies give priority to the collaboration of institutions and researchers to enhance efficiency in processes of research and effectiveness, accordingly addressing pandemic challenges and optimizing funding use (Angelis et al., 2022). The pandemic has, therefore, erected logistical challenges to the conversion of the facilities into research areas, allowing only a limited number of COVID-19 patients. Even with research visits allowed, poor outpatient facilities are a hindrance to productive translational research (Jayaweera et al., 2021). From the perspective of COVID-19 repurposing research in clinical areas, regulatory hurdles and institutional review board approvals make balancing urgent research with ethical standards essential, to protect human subjects (Park et al., 2021). Logistical and regulatory challenges, along with competition, have confronted institutions seeking to repurpose clinical care spaces for COVID-19 research (Miller & Williams 2022).In response, flexibility, and innovation toward urgent needs during the pandemic have been called for. This pandemic has presented ethical considerations in informed consent, especially with regard to vulnerable populations such as the elderly and those who are marginalized. Factors such as social distancing and fear of infection complicate conventional consent processes, emphasizing the need for equity in subject selection and protection (Burgess et al., 2023). Often, subjects of studies performed under such hugely strained circumstances were not fully informed regarding the implications of participation in a study. [Table 5]. Table 5. | Trial ID | Peptide type | Mechanism | Phase | Uses | |---|---|---|---|---| | NCT04751774 | Multi-epitope vaccine | T-cell activation | Phase 2 | Enhanced immunity in elderly | | NCT04535167 | Peptide-drug conjugate | Inhibits viral fusion | Phase 1 | Reduced viral load | Peptide-based COVID-19 therapy: prospects for the future and developing trends The opportunities of customized peptide treatments A significant factor is that peptides can be designed to selectively bind to viral proteins, including the SARS-CoV-2 spike protein, which is essential for the virus's infection of host cells (Bagwe et al., 2022b). This specificity may lead to a reduced likelihood of side effects compared to traditional small-molecule drugs (Shah et al., 2022). Synthesis can occur rapidly, facilitating prompt responses to newly emerging variants (Khavinson et al., 2020c). This is critically important during pandemics, where every second is significant (Di Natale et al., 2020). Engineered peptides can be designed to exhibit enhanced stability, bioavailability, and metabolic resistance (Bagwe et al., 2022b). Peptides serve as active or passive immunizers when used alongside other treatments, including vaccines or monoclonal antibodies, to achieve optimal efficacy against COVID-19 (O’Sullivan et al., 2022). Peptide vaccines can be tailored to enhance immune response to specific viral epitopes in individual patients (Khavinson et al., 2020). Peptide-based therapies also have advantages over monoclonal antibodies for targeting SARS-CoV-2 and its variants (Heo et al., 2024). They are effective against mutations, can rapidly respond to new variants and are more cost-effective and scalable than monoclonal antibodies (R. E. Chen et al., 2021). Real-world comparisons show that peptide-based approaches have potential, while monoclonal antibody therapies have variable efficacy against different strains (Heo et al., 2024b). Recent studies employ immunoinformatic to identify significant B and T cell epitopes from the SARS-CoV-2 spike glycoprotein by analysing viral protein sequences to enhance immune response stimulation (Bagwe et al., 2022b). Research indicates that peptide vaccines can enhance the specificity and efficacy of the immune response to viruses when developed based on natural epitope sequences (L. Wang et al., 2022d). Role of computational biology in accelerating the discovery of peptide drug Computational biology integrates peptide sequence analysis with AI techniques in the design of therapeutic peptides to reduce experimental validation times and predict the binding affinities together with stability (Goles et al., 2024). Computational tools have been used in drug design by predicting three-dimensional peptide-protein interactions. They identify the potential peptide candidates with effective protein binding (Sadybekov and Katritch 2023). Computational biology has been used to improve the properties of the peptides through predictive models (Goles et al., 2024).This iterative design approach is crucial for developing peptides that remain active under physiological conditions while exerting the recommended therapeutic effect (Y. Zhang et al., 2022). The continuous feedback of laboratory results improves the refinement of computational models. Consequently, this makes the predictions more compatible with practical outcomes, speeding up the identification of therapeutic peptides that are viable in a potent manner through combined efforts of computational and experimental methodologies (Y. Zhang et al., 2022). The availability of high-quality data from experiments and the complex nature of the structures that peptides accommodate are among the problems that advanced modelling methods face (Goles et al., 2024). Future predictive modelling advancements will focus on data accessibility and model interpretability, crucial for improved outcomes and societal adoption of methods in drug discovery (Y. Zhang et al., 2022). Machine learning algorithms for the classification of peptide sequences are utilized in large datasets. Its classification is based on various available properties used in the prediction of the peptide's interaction with the target proteins (Goles et al., 2024). Deep learning is used in advanced peptide design to maintain high specificity in sequence and conformation, crucial for therapeutic action (Mulligan, 2020a). The peptide design will be executed using computational tools, utilizing structural information about protein–protein interaction, to create peptides specific to binding regions. Virtual screening for peptide libraries identifies specific candidates for discovery, using generative models like VAEs for de novo peptide sequence design, accelerating the discovery process (Goles et al., 2024). The ability to generate novel, high-specific peptides has excelled the constraints in traditional design methods to predict the complex peptide interactions (Vincenzi et al., 2024). The interaction of computational predictions with experimental data enhances the computational predictions to enhance effectiveness with continuous feedback and refinement in such a manner as to achieve high predictive accuracy in the peptide specificity (Sadybekov and Katritch 2023). This is the iterative process in which, through refinement, the design of the peptides becomes essentially active with minimal side effects (L. Wang et al., 2022e). Rosetta is a software package used in the modeling of macro-molecules that could be utilized in designing peptide macrocycles for enhancing stability and improving membrane permeability. Recent successes have demonstrated its therapeutic potential (Mulligan, 2020b). Deep learning methods, such as CNNs and RNNs, have given rise to the main breakthroughs in the design and structure prediction of peptide drugs to improve their interaction with target proteins (Goles et al., 2024). AlphaFold, developed by DeepMind, predicts protein structure and may be used in designing peptide drugs by more accurate modeling of interactions, thus leading to better-targeted therapeutics with increased efficiency. Structure-based computational virtual screening methodologies of big peptide libraries assess the binding of peptides to targets; thus, enabling the rapid identification of high-affinity peptides (Sadybekov and Katritch 2023). Long-term prospects of peptide therapeutics in pandemic preparation Compared to other small-molecule probes in drug discovery and development, peptides possess certain exclusive target specificities, biochemical characteristics, and low toxicity profiles (L. Wang et al., 2022e). More than 600 peptides are in preclinical and clinical studies, while more than 80 peptide drugs have been approved for a variety of medical disease treatments (Rossino et al., 2023). Peptide-based therapies are also being developed to overcome SARS-CoV-2 spike protein mutations (Magazine et al., 2022). AI-driven peptide design and broad-spectrum approaches are being used to generate and optimize peptides targeting conserved regions or multiple epitopes (Goles et al., 2024). For example, companies like Atomwise focus on broad-spectrum antivirals targeting highly conserved binding sites across various coronavirus species. These approaches highlight the potential of peptide-based interventions to address the evolving pandemic landscape. Peptide vaccines offer rapid adaptability and increased safety in pandemic response because they can be rapidly quick modified to target new variants (Murdocca et al. 2024). They are safer because they lack infectious material, and because they synergize with antivirals and monoclonal antibodies (Purcell et al., 2007). Advances in peptide engineering have increased their efficacy so that peptide-based vaccines such CoVac-1 provide long-term immunity in human trials (Black et al. 2010). Compared with traditional vaccinations, peptide vaccines are considered a valid alternative due to their higher level of safety and less complicated production process (Bagwe et al., 2022c). Systems pharmacology enables the rational design of peptides with improved stability and efficacy, responding to challenges such as rapid metabolism and poor bioavailability (L. Wang et al., 2022f). Multiple virus strain-targeting peptides are currently under development, with their nanoparticle formulations is being studied to improve the bioavailability and effectiveness against emerging pandemic threats (Apostolopoulos et al. 2022). Such a study should be done to enhance treatment efficacy by combining peptide therapeutics with available anti-viral drugs or vaccines and by expanding the scope of therapeutic options available during pandemics (Bagwe et al., 2022c). Developing efficient delivery systems for peptides is in great need. Accordingly, this production process is by far much easier due to such new advances in peptide synthesis modification technologies, and rapid development and deployment could occur in recent health crises (Otvos and Wade 2014). Instability and rapid degradation make application difficult and challenge small molecule drugs, since peptides easily get degraded and their instability renders them difficult to be used in treatments (Rossino et al. 2023). Because of this problem, traditional delivery routes may not be appropriate since peptides are very difficult to use in treatments due to their instabilities and rapid degradation. These peptide drugs, though of therapeutic potential, are surrounded by misconceptions among health caregivers and patients (Otvos and Wade 2014). Innovation in vaccine production addressed costs, supply chain issues and decentralized manufacturing (Boyer et al. 2024). Co-ordinated interventions by national and international stakeholders, treating essential health products as public goods and strengthening researchers in low- and middle-income countries are needed (Ravinetto et al. 2024). AI-based peptide design has considerably facilitated enhanced peptide therapeutics through machine learning models that predict peptide-protein interactions (Nissan et al., 2024b). InSiPS designs new protein sequences for targets, while nanoparticle-based delivery systems such as solid lipid nanoparticles and nanostructured lipid carriers improve oral bioavailability (Dumont, 2022). Lipid-based nanocarriers protect peptides from degradation and enhance intestinal permeation, while polymeric nanoparticles offer biodegradability, biocompatibility, and flexibility for encapsulating various drugs (Md. M. Islam and Raikwar 2024).

Due to the exceptional target selectivity, safety, and flexibility, therapeutic peptides are promising against SARS-CoV-2 and other viral diseases. This study highlights the growing importance of peptide-based strategies, including immunomodulators, peptide vaccines, and antiviral peptides, in addressing the COVID-19 pandemic. Recent improvements in peptide design, made possible by computer programs and creative ways of making compounds, have sped up the creation of peptides that can effectively stop viruses from doing important things. While challenges such as bioavailability and viral mutations remain, ongoing research and clinical trials suggest that peptide therapeutics will play an increasingly crucial role in pandemic preparedness and antiviral drug development, providing new avenues for effective treatments against emerging viral threats. As more research continues, we anticipate that peptide-based therapies will become increasingly important in treating many new viral threats, including COVID-19. Acknowledgments The authors would like to thank the management and administration of SRM Institute of Science and Technology for supporting this work. This work was part of SATU-JRS (2022) initiative and the authors thank SATU. Declarations Conflict of interest The author declares there are no competing interests.

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