Self-Masked Aldehyde Inhibitors: A Novel Strategy for Inhibiting Cysteine Proteases.
J Med Chem
; 64(15): 11267-11287, 2021 08 12.
Article
in English
| MEDLINE | ID: covidwho-1319012
ABSTRACT
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.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Trypanosoma cruzi
/
Cysteine Proteinase Inhibitors
/
Chagas Disease
/
Aldehydes
/
SARS-CoV-2
/
COVID-19 Drug Treatment
Limits:
Humans
Language:
English
Journal:
J Med Chem
Journal subject:
Chemistry
Year:
2021
Document Type:
Article
Affiliation country:
Acs.jmedchem.1c00628
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