Journal of the American Chemical Society · 2006 · 69 citations · 19 references
Life SciencesBiochemistryMedicinal ChemistryMolecular VirologyStructural BiologyVirologyAntiviral AgentsProtein StructureViral StructureVirus StructureAlpha HelicesAlpha-helical Coiled CoilsAlpha-helix MimicsAntiviral Structure-activity RelationshipsHelical ConformationRecombinant Fusion ProteinsViral Fusion ProteinsViral Protein Conformation
A 13-residue peptide sequence from a respiratory syncitial virus fusion protein was constrained in an alpha-helical conformation by fusing two back-to-back cyclic alpha-turn mimetics. The resulting peptide, Ac-(3-->7; 8-->12)-bicyclo-FP[KDEFD][KSIRD]V-NH(2), was highly alpha-helical in water by CD and NMR spectroscopy, correctly positioning crucial binding residues (F488, I491, V493) on one face of the helix and side chain-side chain linkers on a noninteracting face of the helix. This compound displayed potent activity in both a recombinant fusion assay and an RSV antiviral assay (IC(50) = 36 nM) and demonstrates for the first time that back-to-back modular alpha-helix mimetics can produce functional antagonists of important protein-protein interactions.
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