Structure-Guided Design of Potent Inhibitors of SARS-CoV‑2 3CL Protease: Structural, Biochemical, and Cell-Based Studies

The
COVID-19 pandemic is having a major impact on public health
worldwide, and there is an urgent need for the creation of an armamentarium
of effective therapeutics, including vaccines, biologics, and small-molecule
therapeutics, to combat SARS-CoV-2 and emerging variants. Inspection
of the virus life cycle reveals multiple viral- and host-based choke
points that can be exploited to combat the virus. SARS-CoV-2 3C-like
protease (3CLpro), an enzyme essential for viral replication, is an
attractive target for therapeutic intervention, and the design of
inhibitors of the protease may lead to the emergence of effective
SARS-CoV-2-specific antivirals. We describe herein the results of
our studies related to the application of X-ray crystallography, the
Thorpe–Ingold effect, deuteration, and stereochemistry in the
design of highly potent and nontoxic inhibitors of SARS-CoV-2 3CLpro.