A Natural Broad-Spectrum Inhibitor of Enveloped Virus Entry, Restricts SARS-CoV-2 and Influenza a Virus in Preclinical Animal Models

The COVID-19 pandemic has highlighted an urgent need for new antivirals. Targeting host processes co-opted by viruses is an attractive antiviral strategy with a high resistance barrier. Picolinic acid (PA) is a Tryptophan metabolite endogenously produced in mammals. Here we report broad-spectrum antiviral activity of PA against enveloped viruses including Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), Influenza A virus (IAV), Flaviviruses, Herpes simplex virus, and Parainfluenza virus. Mechanistic studies revealed that PA inhibits enveloped virus entry by compromising viral membrane integrity, inhibiting virus-cellular membrane fusion, and interfering with cellular endocytosis. More importantly, in preclinical animal models, PA showed promising antiviral efficacy against SARS-CoV-2 and IAV, especially as an oral prophylactic. Overall, our data establish PA as a broad-spectrum antiviral, with promising preclinical efficacy against pandemic viruses SARS-CoV-2 and IAV.Funding Information: DBT-Wellcome Trust India Alliance (IA/I/18/1/503613), DBT-BIRAC (BT/CS0007/CS/02/20), Crypto Relief Fund, L & T Trust, DST-FIST program, DBT-IISc partnership program (Phase II), Bacteriophage work in the RA laboratory was supported by Ramanujan Fellowship (SB/S2/RJN-037/2017).Conflict of Interests: Indian Institute of Science has filed patents for use of Picolinic acid and its derivatives as broad-spectrum antiviral and listed ST, RN, AB, and RR as inventors.Ethical Approval: This study was conducted in compliance with institutional biosafety guidelines, (IBSC/IISc/ST/17/2020; IBSC/IISc/ST/18/2021), following the Indian Council of Medical Research and Department of Biotechnology recommendations. All experiments involving animals were reviewed and approved by the Institutional Animal Ethics Committee (Ref: IAEC/IISc/ST/784/2020) at the Indian Institute of Science and conducted in Viral Biosafety level-3 facility. The experiments were performed according to CPCSEA (The Committee for Control and Supervision of Experiments on Animals) guidelines.