Department of Biochemistry and Biophysics, Texas A&M University, 300 Olsen Blvd, College Station, Texas 77843, United States.
Department of Chemistry, Texas A&M University, 580 Ross Street, College Station, Texas 77843, United States.
J Med Chem. 2021 Aug 12;64(15):11267-11287. doi: 10.1021/acs.jmedchem.1c00628. Epub 2021 Jul 21.
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-. These SMAIs exerted potent, reversible inhibition of cruzain (* = 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.
半胱氨酸蛋白酶是一类重要的药物靶点，特别是对于像恰加斯病（克氏锥虫）和 COVID-19（3CL 蛋白酶、组织蛋白酶 L）这样的传染病。肽醛已被证明是所有这些蛋白酶的有效抑制剂。然而，醛基固有的高亲电性与安全性问题和代谢不稳定性有关，限制了醛抑制剂作为药物的使用。我们已经为恰加斯病的主要半胱氨酸蛋白酶——克氏锥虫开发了一类新型的自掩蔽醛抑制剂（SMAIs）。这些 SMAIs 对克氏锥虫表现出强大的、可逆的抑制作用（* = 18-350 nM），而在细胞测定中显然保护了游离醛。我们合成了 SMAIs 的前药，这有可能改善它们的药代动力学性质。我们还阐明了 SMAIs 的动力学和化学机制，并将这一策略应用于设计抗 SARS-CoV-2 抑制剂。
