Abstract - Teruna J. Siahaan

Searching for M^pro Enzyme Inhibitors using Immobilized Peptide and Peptidomimetic Libraries

The Corona virus disease 2019 (Covid-19) pandemic caused by the SARS-CoV-2 virus creates tremendous challenges to healthcare systems.  Our goal is to investigate an efficient method to design antiviral drugs that target the SARS-CoV-2 main protease (abbreviated as M^pro) enzyme utilizing a combination of peptide and peptidomimetic libraries.  Thus, the antivirals will be derived from inhibitors of the M^pro enzyme to halt viral proliferation and spreading in the host.  We have screened a peptide library containing 24,000 peptides on controlled pore glass beads (CPG) against the M^pro enzyme and found several optimal and very active substrates with novel sequences that have not been discovered previously.  We also screened a library of 12,139 peptidomimetics and found 36 hit compounds, and the top three hits have IC₅₀’s of 18–28 𝜇M with a similar pharmacophore.  Molecular docking studies suggest that a peptidomimetic KU0431879 with the highest inhibitory activity (18 𝜇M) occupies the S1 and S2 sites (cavities) of the Mpro enzyme active site.  Thus, we are curently designing a hybrid inhibitor(s) using structural features of the optimal substrate and KU0431879.