Siahaan Pilot Project Summary

The Corona virus disease 2019 (Covid19) pandemic caused by the SARS-CoV-2 virus creates tremendous challenges to healthcare systems. Therefore, there is an urgent need to develop methods to diagnose, prevent (e.g., vaccines), and treat (i.e., antiviral drugs) the disease. One of the potential solutions is to design antiviral agents to inhibit the SARS-CoV-2 main protease (abbreviated as Mpro) enzyme activity that is responsible for viral replication. The hope is that the inhibitors can be used as antiviral agents for treating Covid19. The goals of this pilot project are to (a) find optimal substrates of the Mpro enzyme by searching a peptide library consisting of 24,000 peptides and (b) convert the optimal substrates to peptidomimetic inhibitors of the Mpro enzyme using peptide bond bioisosteres. The inhibitors will also be optimized using molecular modeling as well as by replacing the natural amino acids with unnatural ones. Beyond the pilot project, the ability of inhibitors to cross cell membranes will be determined using Caco-2 cells and Vero E6 cell monolayers. Finally, the activity of inhibitors will be evaluated in suppressing replication of SARSCoV-2 in Vero E6 cell monolayers and in female Golden Syrian hamsters. In the future, the pharmacokinetic profiles and formulation of the best inhibitors will be determined.