A Hub Signaling Pathway of Antimicrobial-Antifungal-Anticancer Peptides Axis With Cationic Residue Amino Acids on N, C- Terminals Under 500 Dalton Rule Via Network Pharmacology

Background: Short cationic peptides (SCPs) with therapeutic efficacy of Antimicrobial peptides (AMPs), Antifungal peptides (AFPs), and Anticancer peptides (ACPs) are known as enhancement of host defense system. Here, we investigated the uppermost peptide(s), hub signaling pathway(s), and its associated target(s) through network pharmacology. Method: Firstly, we selected SCPs with positive amino acid residues on N-, C- terminals under 500 Dalton via RStudio. Secondly, EMBOSS pepstats, PASTA 2.0 and Aggrescan were used to remove non- AMPs, after that, ADAM, dbAMP, DBAASP v3.0 , and MLAMP were utilized for AMPs selection. AMPs-targets were identified from both SEA and STP databases. The overlapping targets between the bacteria-responsive targets (TTD and OMIM) and AMPs-targets were visualized by VENNY 2.1. Thirdly, AFPs were filtered through Antifp tool, and TTD and OMIM selected fungal responsive targets. The overlapping targets between AFPs-targets and fungal-responsive targets were visualized by VENNY 2.1. Fourthly, the overlapping targets between cancer-related targets (TTD and OMIM) and fungal-responsive targets were visualized by VENNY 2.1. Fifthly, signaling pathway analysis of overlapping targets was performed via RStudio. Finally, molecular docking study (MDS) was carried out to discover the most potent peptides on a hub signaling pathway. Results: A total of 1,833 SCPs were identified, and AMPs, AFPs, and ACPs filtration suggested that 197 peptides-30 targets, 81 peptides-6 targets, and 59 peptides-4 targets are connected, respectively. The AMPs-AFPs-ACPs axis indicated that 27 peptides-2 targets are associated. Each hub signaling pathway for enhancement of host defense system was "Inactivation of Rap1 signaling pathway on AMPs", "Activation of Notch signaling pathway on AMPs-AFPs axis", and "Inactivation of HIF-1 signaling pathway on AMPs-AFPs-ACPs axis". The most potent peptides were assessed via MDS; finally, HPIK on STAT3, HVTK on NOS2 manifested the HIF-1 signaling pathway's highest affinity. Furthermore, the two peptides have better affinity scores than standard selective inhibitors (Stattic, 1400W). Conclusion: Overall, the most potent SCPs for the host defense system were HPIK on STAT3 and HVTK on NOS2, which might inactivate the HIF-1 signaling pathway.