ABSTRACT
[reaction: see text] Novel tripeptide-derived peptidomimetics 1, 7ab, and 8ab, inspired by templates generated by the structure-generating program GrowMol, were synthesized, shown to inhibit Rhizopus chinensis pepsin, and found by X-ray crystallography to bind to the enzyme in the GrowMol-predicted mode. Repetitive evaluation of the computer-generated templates for synthetic feasibility and optimal enzyme interactions led to the designed compounds.
Subject(s)
Aspartic Acid Endopeptidases/antagonists & inhibitors , Aspartic Acid Endopeptidases/chemistry , Peptides/chemistry , Peptides/metabolism , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism , Aspartic Acid Endopeptidases/metabolism , Computer Simulation , Crystallography, X-Ray , Drug Design , Molecular Mimicry , Peptides/chemical synthesis , Predictive Value of Tests , Protease Inhibitors/chemical synthesis , Protein Conformation , Structure-Activity RelationshipABSTRACT
Major discoveries have been made of new type-I and type-III peptidomimetic inhibitors of peptide-derived systems. Innovative reversible inhibitors of cysteine proteases and renin, and additional examples of peptidomimetic inhibitors of interleukin-1 beta-converting enzyme, neutral endopeptidase, herpes simplex virus protease, thrombin, HIV protease, Ras farnesyltransferase, the RGD motif, Factor Xa and various aspartic proteases have been discovered.
Subject(s)
Drug Design , Enzyme Inhibitors , Molecular Mimicry , Peptides , Aspartic Acid Endopeptidases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Forecasting , Protein ConformationABSTRACT
The unusual amino acid bishomoallylglycine was synthesized and used to form cyclic P3-P1 tripeptide inhibitors via a Grubbs olefin metathesis method. These compounds show micro- to nanomolar inhibition of Rhizopus chinensis pepsin and represent a new class of simplified aspartic protease inhibitors lacking P' residues.