|
|||||
|
|
Tetrapeptides as potent protease inhibitors of Hepatitis C Virus full-length NS3 (protease-helicase/NTPase) |
|
| Authors: | Johansson Anja Poliakov Anton Akerblom Eva Lindeberg Gunnar Winiwarter Susanne Samuelsson Bertil Danielson U Helena Hallberg Anders |
| Institution: | a Department of Medicinal Chemistry, Uppsala University, BMC, Box 574, SE-751 23, Uppsala, Sweden b Department of Biochemistry, Uppsala University, BMC, Box 576, SE-751 23, Uppsala, Sweden c Medivir AB, Lunastigen 7, SE-141 44, Huddinge, Sweden |
| Abstract: | A library of tetrapeptides was evaluated for Hepatitis C Virus NS3 protease inhibitor activity in an in vitro assay system comprising the native bifunctional full-length NS3 (protease-helicase/NTPase) protein. Tetrapeptides with Ki values in the high nanomolar range were identified, for example Suc-Chg-Glu-2-Nal-Cys (Ki=0.27±0.03 μM) and Suc-Dif-Glu-Glu-Cys (Ki=0.40±0.10 μM). Furthermore, it was shown that the inhibitory potencies are not affected significantly by assay ionic strength. As suggested by molecular modelling, potential binding interactions of the tetrapeptide inhibitors with the helicase domain might explain the data and structure–activity relationships thus obtained. Hence, we postulate that the full-length NS3 assay is a relevant system for inhibitor identification, offering new opportunities for inhibitor design. |
| Keywords: | |
| 本文献已被 ScienceDirect PubMed 等数据库收录！ | |