A Systematic Survey of Reversibly Covalent Dipeptidyl Inhibitors of the SARS-CoV-2 Main Protease

被引：13

作者：

Geng, Zhi Zachary ^{[1
]}

Atla, Sandeep ^{[1
]}

Shaabani, Namir ^{[2
]}

Vulupala, Veerabhadra ^{[1
]}

Yang, Kai S. ^{[1
]}

Alugubelli, Yugendar R. ^{[1
]}

Khatua, Kaustav ^{[1
]}

Chen, Peng-Hsun ^{[1
]}

Xiao, Jing ^{[1
]}

Blankenship, Lauren R. ^{[1
]}

Ma, Xinyu R. ^{[1
]}

Vatansever, Erol C. ^{[1
]}

Cho, Chia-Chuan D. ^{[1
]}

Ma, Yuying ^{[1
]}

Allen, Robert ^{[2
]}

Ji, Henry ^{[2
]}

Xu, Shiqing ^{[1
,3
]}

Liu, Wenshe Ray ^{[1
,4
,5
,6
,7
]}

机构：

[1] Texas A&M Univ, Dept Chem, Texas A&M Drug Discovery Lab, College Stn, TX 77843 USA

[2] Sorrento Therapeut Inc, San Diego, CA 92121 USA

[3] Texas A&M Univ, Irma Lerma Rangel Coll Pharm, Dept Pharmaceut Sci, College Stn, TX 77843 USA

[4] Texas A&M Univ, Dept Chem, Dept Biochem & Biophys, Texas A&M Drug Discovery Lab, College Stn, TX 77843 USA

[5] Texas A&M Univ, Coll Med, Dept Mol & Cellular Med, College Stn, TX 77843 USA

[6] University, Inst Biosci & Technol, Houston, TX 77030 USA

[7] Texas A&M Univ, Coll Med, Dept Translat Med Sci, Houston, TX 77030 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 66卷 / 16期

基金：

美国国家卫生研究院;

关键词：

RESPIRATORY SYNDROME; CORONAVIRUS; DISCOVERY;

D O I：

10.1021/acs.jmedchem.3c00221

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

SARS-CoV-2, the COVID-19 pathogen, relies on its mainprotease(M-Pro) for replication and pathogenesis. M-Pro is a demonstrated target for the development of antivirals for SARS-CoV-2.Past studies have systematically explored tripeptidyl inhibitors suchas nirmatrelvir as M-Pro inhibitors. However, dipeptidylinhibitors especially those with a spiro residue at their P2 positionhave not been systematically investigated. In this work, we synthesizedabout 30 dipeptidyl M-Pro inhibitors and characterized themon enzymatic inhibition potency, structures of their complexes withM(Pro), cellular M-Pro inhibition potency, antiviralpotency, cytotoxicity, and in vitro metabolic stability.Our results indicated that M-Pro has a flexible S2 pocketto accommodate inhibitors with a large P2 residue and revealed thatdipeptidyl inhibitors with a large P2 spiro residue such as (S)-2-azaspiro [4,4]nonane-3-carboxylate and (S)-2-azaspiro[4,5]decane-3-carboxylate have favorable characteristics.One compound, MPI60, containing a P2 (S)-2-azaspiro[4,4]nonane-3-carboxylatedisplayed high antiviral potency, low cellular cytotoxicity, and high in vitro metabolic stability.

引用

页码：11040 / 11055

页数：16

共 42 条

[41] Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors
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[42] Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development
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Yang, Fang-Yuan
Zhang, Li
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Feng, Ying-Mei
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[J]. SIGNAL TRANSDUCTION AND TARGETED THERAPY, 2021, 6 (01)

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