RR:C19 Evidence Scale rating by reviewer:
Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.
Antivirals are urgently needed to treat COVID-19, prevent its progression to severe stage, and complement the vaccination efforts to reduce the infection rate and mortality. Development of effective and non-toxic antivirals will benefit our fight with not only the current global pandemic of COVID-19 but also future pandemics. There are different strategies that could be utilized to develop antivirals. Specifically, the authors got the idea from their existing studies to target the cellular entry point of enveloped viruses (e.g., the SARS-CoV-2 that causes COVID-19) using Picolinic Acid (PA), an endogenous byproduct of tryptophan metabolism in humans and other mammals. They demonstrated that PA exhibited in vitro antiviral activity against SARS-CoV-2 and a range of other enveloped viruses (e.g., H1N1 “Swine flu’) with animal and human cell models. Then they showed that PA treatment inhibited Influenza A virus replication and pathogenesis in a preclinical murine model. They also showed evidence for the same effect of PA treatment on SARS-CoV-2 replication and pathogenesis in a preclinical Syrian hamster model. The authors then investigated the antiviral mechanisms of PA, for which their results suggested the disruption of viral membrane and the interference of viral-cellular membrane fusion. Finally, they showed that PA exhibited minimal to no antiviral activity against non-enveloped viruses. Overall, this manuscript provided reliable results and useful information on the potential antiviral effect of PA in a preclinical study with both in vitro and in vivo models. However, there are still major burdens to be crossed and major questions to be answered before this treatment can be applied clinically as a new option to fight the current pandemic and any future ones.
Major concerns are as follows:
1. Future clinical studies will be necessary to establish the toxicity level and evaluate the efficacy of PA for adults and children, as well as people with different population background. In addition, the pharmacodymanics and pharmacokinetics of PA must be established.
2. A comparison with other existing antivirals could provide a clearer picture of efficacy, safety, and the tolerability profile for PA.
3. The current manuscript lacks the description of genome-wide molecular changes after PA treatment. Future investigation of the dynamic changes of genomic and epigenetic profiles (e.g., microRNAs) will enhance our understanding of the underlying mechanisms of the antiviral effect of PA.
In summary, although the authors provided promising results that supported the antiviral effect of PA to various enveloped viruses, including SARS-CoV-2 and influenza, further research and clinical studies will be necessary before making final conclusions on the clinical applicability of PA to fight the current pandemic and any future ones.