Product Inhibition of the Hepatitis C Virus NS3 Protease
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- 作者：Christian Steinkü ; hler ; Gabriella Biasiol ; Mirko Brunetti ; Andrea Urbani ; Uwe Koch ; Riccardo Cortese ; Antonello Pessi ; and Raffaele De Francesco
- 刊名：Biochemistry
- 出版年：1998
- 出版时间：June 23, 1998
- 年：1998
- 卷：37
- 期：25
- 页码：8899 - 8905
- 全文大小：72K
- 年卷期：v.37,no.25(June 23, 1998)
- ISSN：1520-4995
文摘
The nonstructural protein NS3 of the hepatitis C virus (HCV)harbors a serine protease domainthat is responsible for most of the processing events of thenonstructural region of the polyprotein. Itsinhibition is presently regarded as a promising strategy for copingwith the disease caused by HCV. Inthis work, we show that the NS3 protease undergoes inhibition by theN-terminal cleavage products ofsubstrate peptides corresponding to the NS4A-NS4B, NS4B-NS5A, andNS5A-NS5B cleavage sites,whereas no inhibition is observed with a cleavage product of theintramolecular NS3-NS4A junction.The Ki values of the hexamer inhibitoryproducts [Ki(NS4A) = 0.6 
M,Ki(NS5A) = 1.4 M, andKi(NS4B) = 180 M] are lower than the Kmvalues of the respective substrate peptides[Km(NS4A-NS4B)= 10 M, Km(NS5A-NS5B) = 3.8 M,and Km(NS4B-NS5A) > 1000 M].Mutagenesis experimentshave identified Lys136 as an important determinant for product binding.The phenomenon of productinhibition can be exploited to optimize peptide inhibitors of NS3protease activity that may be useful indrug development.
M,Ki(NS5A) = 1.4 M, andKi(NS4B) = 180 M] are lower than the Kmvalues of the respective substrate peptides[Km(NS4A-NS4B)= 10 M, Km(NS5A-NS5B) = 3.8 M,and Km(NS4B-NS5A) > 1000 M].Mutagenesis experimentshave identified Lys136 as an important determinant for product binding.The phenomenon of productinhibition can be exploited to optimize peptide inhibitors of NS3protease activity that may be useful indrug development.