Abstract：
:A new type of thrombin exo-site inhibitor has been designed with enhanced inhibitory potency and increased metabolic stability. With the aid of the model of the structure of the thrombin-hirudin fragment complex [Yue, S.-Y., DiMaio, J., Szewczuk, Z., Purisima, E. O., Ni, F., & Konishi, Y. (1992) Protein Eng. 5, 77-85], cyclic analogs of the hirudin fragment (hirudin55-65) were designed and synthesized. In these analogs, the side chains of appropriately substituted residues, 58 and 61, were joined in order to restrict the conformation of the inhibitor. An analog with an 18-membered lactam ring showed higher antithrombin activity (IC50 = 0.57 microM) than the corresponding analogs with 17- or 16-membered rings and was 2-fold more potent than its linear counterpart. Even 4-fold greater enhancement was obtained when a shorter fragment, hirudin 55-62, was cyclized. This cyclization not only improved the potency but, more importantly, dramatically increased the resistance to proteolytic digestion. Remarkable enhancement of stability to proteolysis was observed for peptide bonds located in the exocyclic linear peptide segments. These results are discussed using molecular modeling.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Szewczuk Z,Gibbs BF,Yue SY,Purisima EO,Konishi Ydoi
10.1021/bi00153a004subject
Has Abstractpub_date
1992-09-29 00:00:00pages
9132-40issue
38eissn
0006-2960issn
1520-4995journal_volume
31pub_type
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