Abstract
Potent inhibitors of human cysteine proteases of the papain family have been made and assayed versus a number of relevant family members. We describe the synthesis of peptide alpha-ketoheterocyclic inhibitors that occupy binding subsites S1'-S3 of the cysteine protease substrate recognition cleft and that form a reversible covalent bond with the Cys 25 nucleophile. X-ray crystal structures of cathepsin K both unbound and complexed with inhibitors provide detailed information on protease/inhibitor interactions and suggestions for the design of tight-binding, selective molecules.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Aspartic Acid / genetics
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Benzoxazoles / chemistry*
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Binding Sites / genetics
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Cathepsin K
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Cathepsins / antagonists & inhibitors*
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Cathepsins / chemistry*
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Cathepsins / genetics
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Crystallography, X-Ray
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Enzyme Inhibitors / chemistry*
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Humans
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Kinetics
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Models, Molecular
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Oligopeptides / chemistry*
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Rabbits
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Tyrosine / genetics
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Valine / genetics
Substances
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Benzoxazoles
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Enzyme Inhibitors
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Oligopeptides
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Recombinant Proteins
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Aspartic Acid
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Tyrosine
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Cathepsins
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CTSK protein, human
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Cathepsin K
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Valine