ArticleJournal of medicinal chemistry2009
The role of amphiphilicity and negative charge in glycoprotein 41 interactions in the hydrophobic pocket.
Article in Journal of medicinal chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed.
- Conformational Stabilization of Gp41-Mimetic Miniproteins Opens Up New Ways of Inhibiting HIV-1 Fusion.International journal of molecular sciences · 2022Article
- A targeted covalent small molecule inhibitor of HIV-1 fusion.Chemical communications (Cambridge, England) · 2021Article
- Enhanced potency of bivalent small molecule gp41 inhibitors.Bioorganic & medicinal chemistry · 2017Article
- 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
- Structure-activity relationship studies of indole-based compounds as small molecule HIV-1 fusion inhibitors targeting glycoprotein 41.Journal of medicinal chemistry · 2014Article
- Identification of fragments targeting an alternative pocket on HIV-1 gp41 by NMR screening and similarity searching.Bioorganic & medicinal chemistry letters · 2013Article
- NMR-assisted computational studies of peptidomimetic inhibitors bound in the hydrophobic pocket of HIV-1 glycoprotein 41.Journal of computer-aided molecular design · 2013Article
- A suite of modular fluorescence assays interrogate the human immunodeficiency virus glycoprotein-41 coiled coil and assist in determining binding mechanism of low molecular weight fusion inhibitors.Assay and drug development technologies · 2012Article
- The conserved residue Arg46 in the N-terminal heptad repeat domain of HIV-1 gp41 is critical for viral fusion and entry.PloS one · 2012Article
- Amphipathic properties of HIV-1 gp41 fusion inhibitors.Current topics in medicinal chemistry · 2011Review
- Biochemistry and biophysics of HIV-1 gp41 - membrane interactions and implications for HIV-1 envelope protein mediated viral-cell fusion and fusion inhibitor design.Current topics in medicinal chemistry · 2011Review
- Resistance of human immunodeficiency virus type 1 to a third-generation fusion inhibitor requires multiple mutations in gp41 and is accompanied by a dramatic loss of gp41 function.Journal of virology · 2011Article
- Broad distribution of energetically important contacts across an extended protein interface.Journal of the American Chemical Society · 2011Article
- Insights into the mechanism of HIV-1 envelope induced membrane fusion as revealed by its inhibitory peptides.European biophysics journal : EBJ · 2011Review
- Origins of resistance to the HIVgp41 viral entry inhibitor T20.Biochemistry · 2010Article
- Design, synthesis, and evaluation of indole compounds as novel inhibitors targeting Gp41.Bioorganic & medicinal chemistry letters · 2010Article
Corrections and comments
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2 authors.
Funding
Abstract
The hydrophobic pocket within the coiled coil domain of HIV-1 gp41 is considered to be a hot-spot suitable for small molecule intervention of fusion, although so far it has yielded only microM inhibitors. Previous peptide studies have identified specific hydrophobic interactions and a Lys-Asp salt bridge as contributing to binding affinity in the pocket. Negative charge appears to be critical for activity of small molecules. We have examined the role of charge and amphiphilic character in the interaction by studying a series of short pocket binding peptides differing in charge, helical content, and in the presence or absence of the Lys-Asp salt bridge, and a series of fatty acid salts with varying charge and hydrocarbon length. Quantitative binding analysis revealed that long-range electrostatic forces and a greasy nonspecific hydrophobic interaction were sufficient for microM potency. The results suggest that an extended interaction site may be necessary for higher potency. We examined a region of the coiled coil immediately C-terminal to the pocket and found that specific salt bridge and hydrogen bond networks may reside in this region. Negatively charged groups extended toward or beyond the C-terminus of the pocket could therefore result in improved low molecular weight fusion inhibitors.
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