Mechanistic insights into dengue virus inhibition by a clinical trial compound NITD-688

• 成果类型: Article
• 署名作者: Wang, Yan; Sun, Long; Fernandes, Luciana; Wang, Yu-Hsiu; Zou, Jing; Franklin, Samuel J.; Hu, Yanping; Palmer, Lee K.; Yeung, Jason; Barriga, Daniela; Russell, William K.; Moquin, Stephanie A.; Shi, Pei-Yong; Skepper, Colin; Xie, Xuping
• 署名单位: University of Texas System; University of Texas Medical Branch Galveston; University of Texas System; University of Texas Medical Branch Galveston; Novartis; Novartis USA; University of Texas System; University of Texas Medical Branch Galveston
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14313
• DOI: 10.1073/pnas.2426922122
• 发表日期: 2025-04-01
• 关键词: nonstructural proteins ns1; ns4b protein; membrane topology; rna; DISCOVERY

摘要

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 nano-molar 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.