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.

JOURNAL ARTICLE Amino Acid Sequence Anti-HIV Agents/CHEMISTRY/*CHEMICAL SYNTHESIS/METABOLISM/ *PHARMACOLOGY Cell Fusion/DRUG EFFECTS Cell Line Chimeric Proteins/CHEMISTRY/METABOLISM Combinatorial Chemistry Techniques Dose-Response Relationship, Drug Drug Design Drug Screening Human HIV Envelope Protein gp41/CHEMISTRY/*METABOLISM/PHARMACOLOGY HIV-1/*DRUG EFFECTS/METABOLISM/PHYSIOLOGY Ligands Membrane Fusion/*DRUG EFFECTS Models, Molecular Molecular Sequence Data Peptide Fragments/CHEMISTRY/METABOLISM/PHARMACOLOGY *Peptide Library Protein Binding/DRUG EFFECTS Protein Structure, Secondary Support, Non-U.S. Gov't Support, U.S. Gov't, P.H.S.

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