PXD053801

PXD053801 is an original dataset announced via ProteomeXchange.

Title	Mechanistic Insights into Dengue Virus Inhibition by a Clinical Trial Compound NITD-688
Description	Dengue, caused by the dengue virus (DENV), presents a significant public health challenge with limited effective treatments. NITD-688 is a potent pan-serotype 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 nonstructural protein 4B (NS4B) with nanomolar affinities across all four DENV serotypes. This binding specifically disrupts the interaction between NS4B and nonstructural protein 3 (NS3), without affecting interactions with other viral or host proteins. NITD-688-resistant mutations in NS4B reduce NITD-688 binding to NS4B and its disruption of the NS4B/NS3 interaction. Mechanistically, NITD-688 blocks the interaction of NS3 with a cytosolic loop within NS4B and disrupts both the formation and pre-existing NS4B/NS3 complexes in vitro and in DENV-infected cells, ultimately inhibiting viral replication. This characteristic enables NITD-688 to remain effective even with delayed treatment, distinguishing it from JNJ-1802, another clinically studied NS4B inhibitor. Moreover, combining NITD-688 with either JNJ-1802 or an NS5 polymerase inhibitor synergistically inhibits DENV-2 infection. 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.
HostingRepository	PRIDE
AnnounceDate	2025-10-06
AnnouncementXML	Submission_2025-10-05_17:07:44.856.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD053801
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Lee Palmer
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606; scientific name: Dengue virus; NCBI TaxID: NCBITaxon:12637;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2024-07-09 08:17:30	ID requested
⏵ 1	2025-10-05 17:07:45	announced

10.1073/pnas.2426922122;

Wang Y, Sun L, Fernandes L, Wang YH, Zou J, Franklin SJ, Hu Y, Palmer LK, Yeung J, Barriga D, Russell WK, Moquin SA, Shi PY, Skepper C, Xie X, Mechanistic insights into dengue virus inhibition by a clinical trial compound NITD-688. Proc Natl Acad Sci U S A, 122(13):e2426922122(2025) [pubmed]

10.6019/PXD053801;

submitter keyword: NS3, JNJ-1802, NS4B, viral replication, antiviral,DENV, flavivirus, NITD-688

William Russell
contact affiliation	Mass Spectrometry Facility, Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, USA
contact email	wirussel@utmb.edu
lab head
Lee Palmer
contact affiliation	University of Texas Medical Branch at Galveston
contact email	lkpalmer@utmb.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD053801
     1. Label: PRIDE project
     2. Name: Mechanistic Insights into Dengue Virus Inhibition by a Clinical Trial Compound NITD-688