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

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 anal-ysis 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.(c) 2022 Elsevier Inc. All rights reserved.

Automated summary

Dengue virus (DENV) is the most widespread arbovirus in the world. Potent NS2B-NS3 covalent inhibitors with increased enzymatic activities and no cellular toxicity have been discovered. Comprehensive structure-activity relationship analysis provides informative understanding of the binding modes of covalent inhibitors targeting NS2B-NS3.