This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dimasi, N. Articles by Sollazzo, M. Search for Related Content PubMed PubMed Citation Articles by Dimasi, N. Articles by Sollazzo, M.

 Previous Article  |  Next Article 

J. Virol., 10 1997, 7461-7469, Vol 71, No. 10
Copyright © 1997, American Society for Microbiology

Characterization of engineered hepatitis C virus NS3 protease inhibitors affinity selected from human pancreatic secretory trypsin inhibitor and minibody repertoires

N Dimasi, F Martin, C Volpari, M Brunetti, G Biasiol, S Altamura, R Cortese, R De Francesco, C Steinkuhler and M Sollazzo
Department of Biotechnology, Istituto di Ricerche di Biologia Molecolare P. Angeletti, Pomezia, Rome, Italy.

Given the extent of hepatitis C virus (HCV) infection as a worldwide health problem and the lack of effective treatment, the development of anti-HCV drugs is an important and pressing objective. Previous studies have indicated that proteolytic events mediated by the NS3 protease of HCV are fundamental to the generation of an active viral replication apparatus, as unequivocably demonstrated for flaviviruses. As a result, the NS3 protease has become a major target for discovering anti-HCV drugs. To gain further insight into the biochemical and biophysical properties of the NS3 enzyme binding pocket(s) and to generate biological tools for developing antiviral strategies, we decided to engineer macromolecular ligands of the NS3 protease domain. Phage- displayed repertoires of minibodies ("minimized" antibody-like proteins) and human pancreatic secretory trypsin inhibitor were sampled by using the recombinant NS3 protease domain as a ligate molecule. Two protease inhibitors were identified and characterized biochemically. These inhibitors show marked specificity for the viral protease and potency in the micromolar range but display different mechanisms of inhibition. The implications for prospective development of low- molecular-weight inhibitors of this enzyme are discussed.

This article has been cited by other articles:

• Ueno, T., Misawa, S., Ohba, Y., Matsumoto, M., Mizunuma, M., Kasai, N., Tsumoto, K., Kumagai, I., Hayashi, H. (2000). Isolation and Characterization of Monoclonal Antibodies That Inhibit Hepatitis C Virus NS3 Protease. J. Virol. 74: 6300-6308 [Abstract] [Full Text]  
• Leyssen, P., De Clercq, E., Neyts, J. (2000). Perspectives for the Treatment of Infections with Flaviviridae. Clin. Microbiol. Rev. 13: 67-82 [Abstract] [Full Text]  
• Martin, F., Steinkuhler, C., Brunetti, M., Pessi, A., Cortese, R., De Francesco, R., Sollazzo, M. (1999). A loop-mimetic inhibitor of the HCV-NS3 protease derived from a minibody. Protein Eng Des Sel 12: 1005-1011 [Abstract] [Full Text]  
• Patick, A. K., Potts, K. E. (1998). Protease Inhibitors as Antiviral Agents. Clin. Microbiol. Rev. 11: 614-627 [Abstract] [Full Text]