期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 64, 期 15, 页码 11267-11287出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c00628
关键词
-
资金
- NIH [R21 AI127634, R01 GM129076]
- Texas A&M AgriLife Research
A novel class of self-masked aldehyde inhibitors has been developed for the major cysteine protease of Chagas disease, showing potent and reversible inhibition while potentially improving pharmacokinetic properties. The study also elucidated the kinetic and chemical mechanism of these inhibitors and applied the strategy to design anti-SARS-CoV-2 drugs.
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 (K-i* = 18350 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据