ArticleBioorganic & medicinal chemistry letters2013
Identification of fragments targeting an alternative pocket on HIV-1 gp41 by NMR screening and similarity searching.
Article in Bioorganic & medicinal chemistry letters, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Helical sulfonyl-γ-AApeptides for the inhibition of HIV-1 fusion and HIF-1α signaling.RSC medicinal chemistry · 2024Review
- Targeting a Conserved Lysine in the Hydrophobic Pocket of HIV-1 gp41 Improves Small Molecule Antiviral Activity.Viruses · 2022Article
- Structural and Functional Characterization of the Secondary Mutation N126K Selected by Various HIV-1 Fusion Inhibitors.Viruses · 2020Article
- N-Substituted Pyrrole Derivative 12m Inhibits HIV-1 Entry by Targeting Gp41 of HIV-1 Envelope Glycoprotein.Frontiers in pharmacology · 2019Article
- Exceptional potency and structural basis of a T1249-derived lipopeptide fusion inhibitor against HIV-1, HIV-2, and simian immunodeficiency virus.The Journal of biological chemistry · 2018Article
- Mechanism of HIV-1 Resistance to an Electronically Constrained α-Helical Peptide Membrane Fusion Inhibitor.Journal of virology · 2018Article
- Enfuvirtide (T20)-Based Lipopeptide Is a Potent HIV-1 Cell Fusion Inhibitor: Implications for Viral Entry and Inhibition.Journal of virology · 2017Article
- Systematic Targeting of Protein-Protein Interactions.Trends in pharmacological sciences · 2016Review
- Inhibition of HIV Entry by Targeting the Envelope Transmembrane Subunit gp41.Current HIV research · 2016Review
- Swapped-domain constructs of the glycoprotein-41 ectodomain are potent inhibitors of HIV infection.ACS chemical biology · 2015Article
- Design and characterization of swapped-domain constructs of HIV-1 glycoprotein-41 as receptors for drug discovery.Protein engineering, design & selection : PEDS · 2015Article
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2 authors.
Funding
Abstract
The HIV-1 envelope glycoprotein gp41 fusion intermediate is a promising drug target for inhibiting viral entry. However, drug development has been impeded by challenges inherent in mediating the underlying protein-protein interaction. Here we report on the identification of fragments that bind to a C-terminal sub-pocket adjacent to the well-known hydrophobic pocket on the NHR coiled coil. Using a specifically designed assay and ligand-based NMR screening of a fragment library, we identified a thioenylaminopyrazole compound with a dissociation constant of ~500 μM. Interaction with the C-terminal sub-pocket was confirmed by paramagnetic relaxation enhancement NMR experiments, which also yielded the binding mode. Shape-based similarity searching detected additional phenylpyrazole and phenyltriazole fragments within the library, enriching the hit rate over random screening, and revealing molecular features required for activity. Discovery of the novel scaffolds and binding mechanism suggests avenues for extending the interaction surface and improving the potency of a hydrophobic pocket binding inhibitor.
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