Abstract
The trimeric, alpha-helical coiled-coil core of the HIV-1 gp41 ectodomain is thought to be part of a transient, receptor-triggered intermediate in the refolding of the envelope glycoprotein into a fusion-active conformation. In an effort to discover small organic inhibitors that block gp41 activation, we have generated a biased combinatorial chemical library of non-natural binding elements targeted to the gp41 core. From this library of 61,275 potential ligands, we have identified elements that, when covalently attached to a peptide derived from the gp41 outer-layer alpha-helix, contribute to the formation of a stable complex with the inner core and to inhibition of gp41-mediated cell fusion.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Anti-HIV Agents / chemical synthesis*
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Anti-HIV Agents / chemistry
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Anti-HIV Agents / metabolism
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Anti-HIV Agents / pharmacology*
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Cell Fusion
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Cell Line
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Combinatorial Chemistry Techniques
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Dose-Response Relationship, Drug
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Drug Design
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Drug Evaluation, Preclinical
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Enfuvirtide
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HIV Envelope Protein gp41 / chemistry
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HIV Envelope Protein gp41 / metabolism*
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HIV Envelope Protein gp41 / pharmacology
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HIV-1 / drug effects*
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HIV-1 / metabolism
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HIV-1 / physiology
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Humans
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Ligands
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Membrane Fusion / drug effects*
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Models, Molecular
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Molecular Sequence Data
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Peptide Fragments / chemistry
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Peptide Fragments / metabolism
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Peptide Fragments / pharmacology
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Peptide Library*
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Protein Binding / drug effects
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Protein Structure, Secondary
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / metabolism
Substances
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Anti-HIV Agents
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HIV Envelope Protein gp41
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Ligands
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Peptide Fragments
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Peptide Library
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Recombinant Fusion Proteins
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Enfuvirtide