Abstract
A series of substituted biphenyl ethylene ether compounds has been designed to target the gp41N-trimer in order to inhibit formation of the six-helical bundle that represents the end state of gp41-mediated viral fusion. A size exclusion HPLC based helical bundle formation (HBF) assay was developed to evaluate in vitro inhibitory affinity of the inhibitors. The most potent compound 1 had an IC(50) of 31microM. The binding of compound 1 to the proposed hydrophobic pocket of gp41 was further validated by site-directed peptide mutagenesis experiments.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anti-HIV Agents / chemical synthesis
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Anti-HIV Agents / chemistry*
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Anti-HIV Agents / pharmacology
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Binding Sites
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Computer Simulation
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Crystallography, X-Ray
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Drug Design
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Ethers / chemical synthesis
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Ethers / chemistry*
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Ethers / pharmacology
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HIV Envelope Protein gp41 / antagonists & inhibitors
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HIV Envelope Protein gp41 / chemistry*
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HIV Envelope Protein gp41 / metabolism
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Humans
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Hydrophobic and Hydrophilic Interactions
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Ligands
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Naphthalenes / chemical synthesis
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Naphthalenes / chemistry*
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Naphthalenes / pharmacology
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Protein Binding
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Protein Structure, Tertiary
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Tetrazoles / chemical synthesis
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Tetrazoles / chemistry*
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Tetrazoles / pharmacology
Substances
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Anti-HIV Agents
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Ethers
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HIV Envelope Protein gp41
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Ligands
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Naphthalenes
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Tetrazoles