Identification of novel target sites and an inhibitor of the dengue virus E protein

Yennamalli, Ragothaman M.; Subbarao, Naidu; Kampmann, T.; McGeary, Ross P.; Young, Paul R.; Kobe, Boštjan

doi:10.1007/s10822-009-9263-6

Cited by 72 publications

(69 citation statements)

References 49 publications

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“…Schmidt and co-workers suggested that the conformational transition from a pre-fusion arrangement to a post-fusion trimer will require removal of the ligand, imposing a barrier to completion of the fusion process. For this reason, in silico screens found potential pocket-binding compounds, that in some cases yielded active inhibitors [60–63]. Thus the electrostatic interaction of R1074 in a well-defined cavity at the base of the stem region and our functional data showing its role in trimer stabilization and membrane fusion activity suggest that this cavity might be a target for small molecule fusion inhibitors.…”

Section: Resultsmentioning

confidence: 96%

Crystal Structure of Glycoprotein C from a Hantavirus in the Post-fusion Conformation

et al. 2016

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Hantaviruses are important emerging human pathogens and are the causative agents of serious diseases in humans with high mortality rates. Like other members in the Bunyaviridae family their M segment encodes two glycoproteins, GN and GC, which are responsible for the early events of infection. Hantaviruses deliver their tripartite genome into the cytoplasm by fusion of the viral and endosomal membranes in response to the reduced pH of the endosome. Unlike phleboviruses (e.g. Rift valley fever virus), that have an icosahedral glycoprotein envelope, hantaviruses display a pleomorphic virion morphology as GN and GC assemble into spikes with apparent four-fold symmetry organized in a grid-like pattern on the viral membrane. Here we present the crystal structure of glycoprotein C (GC) from Puumala virus (PUUV), a representative member of the Hantavirus genus. The crystal structure shows GC as the membrane fusion effector of PUUV and it presents a class II membrane fusion protein fold. Furthermore, GC was crystallized in its post-fusion trimeric conformation that until now had been observed only in Flavi- and Togaviridae family members. The PUUV GC structure together with our functional data provides intriguing evolutionary and mechanistic insights into class II membrane fusion proteins and reveals new targets for membrane fusion inhibitors against these important pathogens.

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Section: Resultsmentioning

confidence: 96%

Crystal Structure of Glycoprotein C from a Hantavirus in the Post-fusion Conformation

et al. 2016

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“…Several groups have previously used in silico screening to identify small molecules that bind in a proposed “hinge region” pocket discovered in the high resolution crystal structure of soluble DENV2 E prefusion dimer crystallized with the detergent beta- octoglucoside (Modis, et al, 2003). Compounds identified in these virtual screens include, among other compounds, 2,4-disubstituted pyrimidines and quinazolines that inhibit DENV entry (Kampmann, et al, 2009; Poh, et al, 2009; Wang, et al, 2009; Yennamalli, et al, 2009; Zhou, et al, 2008). While these compounds are proposed to interact with the hinge region pocket, structural data or resistance mutations validating this as the binding site and documenting that this interaction results in inhibition of membrane fusion have been lacking.…”

Section: Discussionmentioning

confidence: 99%

GNF-2 Inhibits Dengue Virus by Targeting Abl Kinases and the Viral E Protein

Clark

Miduturu

Schmidt

et al. 2016

Cell Chemical Biology

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Summary Dengue virus infects over 300 million people annually, yet there is no widely protective vaccine or drugs against the virus. Efforts to develop antivirals against classical targets such as the viral protease and polymerase have not yielded drugs that have advanced to the clinic. Here we show that the allosteric Abl kinase inhibitor GNF-2 interferes with dengue virus replication via activity mediated by cellular Abl kinases but additionally blocks viral entry via an Abl-independent mechanism. To characterize this newly discovered antiviral activity, we developed disubstituted pyrimidines that block dengue virus entry with structure-activity relationships distinct from those driving kinase inhibition. We demonstrate that biotin- and fluorophore-conjugated derivatives of GNF-2 interact with the dengue glycoprotein, E, in the prefusion conformation that exists on the virion surface and that this interaction inhibits viral entry. This study establishes GNF-2 as an antiviral compound with polypharmacological activity and provides ‘lead’ compounds for further optimization efforts.

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“…In particular, the crystal structure of the DENV2 E protein displays a ligand-binding pocket that was occupied by a detergent molecule, n-octyl-b-D-glucoside (b-OG) [15]. This initiated several groups to identify and optimize potential inhibitors targeting this region of E protein for DENV [16,17,18,19,20] and YFV [21,22,23], mainly through a virtual screening approach. Although different classes of compounds were identified that inhibited DENV, only a handful worked on WNV.…”

Section: Inhibitors Of Viral Targetsmentioning

confidence: 99%

West Nile Virus Drug Discovery

Lim

Shi

2013

Viruses

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The outbreak of West Nile virus (WNV) in 1999 in the USA, and its continued spread throughout the Americas, parts of Europe, the Middle East and Africa, underscored the need for WNV antiviral development. Here, we review the current status of WNV drug discovery. A number of approaches have been used to search for inhibitors of WNV, including viral infection-based screening, enzyme-based screening, structure-based virtual screening, structure-based rationale design, and antibody-based therapy. These efforts have yielded inhibitors of viral or cellular factors that are critical for viral replication. For small molecule inhibitors, no promising preclinical candidate has been developed; most of the inhibitors could not even be advanced to the stage of hit-to-lead optimization due to their poor drug-like properties. However, several inhibitors developed for related members of the family Flaviviridae, such as dengue virus and hepatitis C virus, exhibited cross-inhibition of WNV, suggesting the possibility to re-purpose these antivirals for WNV treatment. Most promisingly, therapeutic antibodies have shown excellent efficacy in mouse model; one of such antibodies has been advanced into clinical trial. The knowledge accumulated during the past fifteen years has provided better rationale for the ongoing WNV and other flavivirus antiviral development.

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Identification of novel target sites and an inhibitor of the dengue virus E protein

Cited by 72 publications

References 49 publications

Crystal Structure of Glycoprotein C from a Hantavirus in the Post-fusion Conformation

Crystal Structure of Glycoprotein C from a Hantavirus in the Post-fusion Conformation

GNF-2 Inhibits Dengue Virus by Targeting Abl Kinases and the Viral E Protein

West Nile Virus Drug Discovery

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