Structure-Guided Design of Conformationally Constrained Cyclohexane Inhibitors of Severe Acute Respiratory Syndrome Coronavirus‑2 3CL Protease

A series
of nondeuterated and deuterated dipeptidyl aldehyde and
masked aldehyde inhibitors that incorporate in their structure a conformationally
constrained cyclohexane moiety was synthesized and found to potently
inhibit severe acute respiratory syndrome coronavirus-2 3CL protease
in biochemical and cell-based assays. Several of the inhibitors were
also found to be nanomolar inhibitors of Middle East respiratory syndrome
coronavirus 3CL protease. The corresponding latent aldehyde bisulfite
adducts were found to be equipotent to the precursor aldehydes. High-resolution
cocrystal structures confirmed the mechanism of action and illuminated
the structural determinants involved in binding. The spatial disposition
of the compounds disclosed herein provides an effective means of accessing
new chemical space and optimizing pharmacological activity. The cellular
permeability of the identified inhibitors and lack of cytotoxicity
warrant their advancement as potential therapeutics for COVID-19.