Transforming bivalent ligands into retractable enzyme inhibitors through polypeptide-protein interactions.
The concept of bivalent polypeptides with controllable flexible linkers is demonstrated through the design of a new generation of 'antidote'-reversible inhibitors of thrombin. These molecules contain two binding moieties, each of which in isolation has only a moderate affinity of binding, which are linked together by a flexible peptide bridge. We show that activities of the potent bivalent inhibitors of thrombin can be reversed by the specific, but much weaker, binding of the linker moiety to protein 'antidotes'.
Tolkatchev
Dmitri
D
Bio-NMR and Protein Research Group, Biotechnology Research Institute, National Research Council of Canada, 6100 Royalmount Avenue, Montreal, Que., Canada H4P 2R2.
Vinogradova
Anna
A
Ni
Feng
F
D000595:Amino Acid Sequence; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D011506:Proteins / Q000737:chemistry / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors*
D008024:Ligands; D010455:Peptides; D011506:Proteins; D015842:Serine Proteinase Inhibitors; D013917:Thrombin