The emergence of new variants coupled with rapidly mutating RNA viruses leads to drug resistance and the need for the continued discovery of new anti-SARS-CoV-2 therapeutic agents to mitigate the adverse impacts of the COVID-19 pandemic. Our efforts in developing potential new drug candidates against SARS-CoV-2 focus on multi-targeted computer-aided drug design (CADD). Drugs targeting essential viral proteins are preferred over antivirals targeting host cells to avoid or minimize adverse effects on the host, as they show higher specificity toward the virus. α-Aminocyclobutanones can serve as peptidomimetics, and due to the ring strain, the ketone carbonyl is more electrophilic than an unstrained ketone. N-Functionalized 2-aminocyclobutanones are reported to show inhibitory potencies against drug target enzymes, including β-lactamases, serine proteases, and esterases. We identified a set of hit cyclobutanone compounds against the SARS-CoV-2 enzymes helicase and the main protease (3CLPro) enabled by virtual high-throughput screening of a synthesized cyclobutanone library (n=298 with 1432 3D conformers) against seven identified druggable SARS-CoV-2 target enzymes utilizing the Schrodinger suite (LLC 2022-1)2 and the Molecular Operating Environment (MOE).3 Antiviral activity of N-functionalized 2-aminocyclobutanone hits, as well as subsequent hit-derived analogs, were tested in vitro using SARS-CoV-2 virus in BSL-3 through a cell survival assay measuring viral copies as well as nuclear count to measure the inherent efficacy and toxicity of these antiviral agents. Six rationally designed peptidomimetic cyclobutanone hits against helicase and three benzimidazole-based covalent inhibitors of the main protease show promising antiviral activities with minimal or no toxic effects on mammalian host cells in the cell survival assay, validating out multi-target CADD approach in developing small-molecule antivirals against SARS-CoV-2. Currently, inhibitory potencies of these inhibitors are being tested against new variants and their specificity using in vitro enzymatic assays to establish the dose-response profile against both SARS-CoV-2 helicase and main protease. Progress in the design and synthesis of highly potent and selective inhibitors with improved efficacy against SARS-CoV-2 with SAR optimization enabled by CADD will be reported.

Design and synthesis of inhibitors targeting Sars-Cov-2 helicase and main protease through computer-aided drug design

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.