Discovery of highly potent DENV NS2B-NS3 covalent inhibitors containing a phenoxymethylphenyl residue

Jiawei Cheng; Shasha Feng; Yaoliang Zhang; Tong Ding; Hailun Jiang; Zhigang Zhang; Jian Wang; Xuejun Wang; Maosheng Cheng

doi:10.1016/j.bbrc.2022.08.060

Discovery of highly potent DENV NS2B-NS3 covalent inhibitors containing a phenoxymethylphenyl residue

Biochem Biophys Res Commun. 2022 Oct 30:627:214-219. doi: 10.1016/j.bbrc.2022.08.060. Epub 2022 Aug 26.

Authors

Jiawei Cheng¹, Shasha Feng¹, Yaoliang Zhang¹, Tong Ding¹, Hailun Jiang¹, Zhigang Zhang¹, Jian Wang¹, Xuejun Wang², Maosheng Cheng³

Affiliations

¹ Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China; Key Laboratory of Intelligent Drug Design and New Drug Discovery of Liaoning Province, Shenyang Pharmaceutical University, Shenyang, 110016, China.
² State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.
³ Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China; Key Laboratory of Intelligent Drug Design and New Drug Discovery of Liaoning Province, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: mscheng@syphu.edu.cn.

PMID: 36058105
DOI: 10.1016/j.bbrc.2022.08.060

Abstract

Dengue virus (DENV) has developed rapidly in the past few decades and has been becoming the most widespread arbovirus in the world. The vital role of NS2B-NS3 in virus replication and maturation of relevant proteins makes it the most promising target for anti-DENV drug discovery, although none of NS2B-NS3 inhibitors have been approved for the market so far. In this study, potent NS2B-NS3 covalent inhibitors were discovered via chemical modification of a published covalent inhibitor WSL-01 (IC₅₀ = 129 nM), yielding promising analogs WSL-75 and WSL-84 (IC₅₀ = 24.8 nM and IC₅₀ = 32.89 nM, respectively) with more than 10-fold increased enzymatic activities compared to the lead compound, and no evident cellular toxicity was observed. Further comprehensive structure-activity relationship analysis through covalent docking and molecular dynamics simulation provides informative understanding of the binding modes of covalent inhibitors targeting NS2B-NS3, which would be beneficial for novel NS2B-NS3 inhibitory development.

Keywords: Covalent inhibitor; Dengue virus (DENV); Molecular simulation; NS2B-NS3.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents / chemistry
Antiviral Agents / pharmacology
Dengue Virus* / metabolism
Molecular Docking Simulation
Protease Inhibitors / pharmacology
Serine Endopeptidases / metabolism
Viral Nonstructural Proteins / chemistry

Substances

Antiviral Agents
Protease Inhibitors
Viral Nonstructural Proteins
Serine Endopeptidases