Organic Letters · 2012 · 49 citations · 23 references
PharmacyBiochemistryMedicinal ChemistryDrug DesignDrug DiscoveryEnzymologyEnzyme InhibitionMacrocycle SynthesisMacrocyclic Drug DesignPeptidomimetic DesignProtein StructureProteolytic EnzymesCalpain ActivityCalpain SystemCalpain-mediated ProteolysisMacrocycle Library SynthesisMacrocyclic PeptidomimeticsPeptidomimetic MacrocyclesProtease Catalytic MechanismsStructure-based Peptidomimetics
New peptidic templates constrained into a β-strand geometry by linking acetylene and azide containing P(1) and P(3) residues of a tripeptide by Huisgen cycloaddition are presented. The conformations of the macrocycles are defined by NMR studies and those that best define a β-strand are shown to be potent inhibitors of the protease calpain. The β-strand templates presented and defined here are prepared under optimized conditions that should be suitable for targeting a range of proteases and other applications requiring such a geometry.
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