Wang, Yan, Son, Long, Fernandes, Luciana, Wang, Yu-Hsiu, Zou, Jing, Franklin, Samuel, Hu, Yanping, Palmer, Lee, Yeung, Jason, Barriga, Daniela, Russel, William, Moquin, Stephanie, Shi, Pei-Yong, Skepper, Colin and Xie, Xuping (2025) Mechanistic insights into dengue virus inhibition by a clinical trial compound NITD-688. Proceedings of the National Academy of Sciences of the United States of America, 122 (13). e2426922122. ISSN 1091-6490

Abstract

Dengue, caused by the dengue virus (DENV), presents a significant public health challenge with limited effective treatments. NITD-688 is a potent panserotype DENV inhibitor currently in Phase II clinical trials. However, its mechanism of action is not fully understood. Here, we present the molecular details of how NITD-688 inhibits DENV. NITD-688 binds directly to the nonstructural protein 4B (NS4B) with nanomolar affinities across all four DENV serotypes and specifically disrupts the interaction between NS4B and nonstructural protein 3 (NS3) without significantly changing the interactions between NS4B and other viral or host proteins. NS4B mutations that confer resistance to NITD-688 reduce both NITD-688 binding to NS4B and disruption of the NS4B/NS3 interaction. Specifically, NITD-688 blocks the interaction of NS3 with a cytosolic loop within NS4B. This inhibits the formation of new NS4B/NS3 complexes and disrupts preexisting complexes in vitro and DENV-infected cells, ultimately inhibiting viral replication. Consistent with this mechanism, NITD-688 retains greater potency in cellular assays with delayed treatment compared to JNJ-1802, another NS4B inhibitor that has been studied in Phase II clinical trials. Together, these findings provide critical insights into the mechanism of action of NITD-688, facilitating the development of novel flavivirus NS4B inhibitors and informing future clinical interventions against DENV.

Item Type:	Article
Keywords:	Dengue Virus Viral Nonstructural Proteins Humans Antiviral Agents Dengue Virus Replication Protein Binding Mutation Drug Resistance, Viral Membrane Proteins
Date Deposited:	29 Apr 2025 00:45
Last Modified:	29 Apr 2025 00:45
URI:	https://oak.novartis.com/id/eprint/55842