Self-Masked Aldehyde Inhibitors: A Novel Strategy for Inhibiting Cysteine Proteases

Cysteine
proteases comprise an important class of drug targets,
especially for infectious diseases such as Chagas disease (cruzain)
and COVID-19 (3CL protease, cathepsin L). Peptide aldehydes have proven
to be potent inhibitors for all of these proteases. However, the intrinsic,
high electrophilicity of the aldehyde group is associated with safety
concerns and metabolic instability, limiting the use of aldehyde inhibitors
as drugs. We have developed a novel class of self-masked aldehyde
inhibitors (SMAIs) for cruzain, the major cysteine protease of the
causative agent of Chagas diseaseTrypanosoma
cruzi. These SMAIs exerted potent, reversible inhibition
of cruzain (Ki* = 18–350 nM) while
apparently protecting the free aldehyde in cell-based assays. We synthesized
prodrugs of the SMAIs that could potentially improve their pharmacokinetic
properties. We also elucidated the kinetic and chemical mechanism
of SMAIs and applied this strategy to the design of anti-SARS-CoV-2
inhibitors.