Synthetic bulky NS4A peptide variants bind to and inhibit HCV NS3 protease

Journal of Advanced Research

Hani Z. Asfour¹  Abdelsattar M. Omar²  Stefan T. Arold³  Maan T. Khayat⁴  Mahmoud A. Elfaky⁵  Moustafa E. El-Araby⁵  Sameh H. Soror⁵  Faida Bamane⁶ 

[1] Center for Scientific Excellence Helwan Structural Biology Research (HSBR), Faculty of Pharmacy, Helwan University, Ain Helwan, P.O. 11795, Cairo, Egypt;Corresponding author.;Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt;Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Helwan University, Ain Helwan, P.O. 11795, Cairo, Egypt;Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Alsulaymanyah, Jeddah 21589, Saudi Arabia;King Abdullah University of Science and Technology, Computational Bioscience Research Center, Division of Biological and Environmental Sciences and Engineering, Thuwal 23955-6900, Saudi Arabia;

关键词: DSLS;    Fluorescence anisotropy;    Allosteric inhibitor;    HCV;    NS3/4A;    Peptide mutants;   

DOI  :  

来源: DOAJ

【 摘 要 】

NS4A is a non-structural multi-tasking small peptide that is essential for HCV maturation and replication. The central odd-numbered hydrophobic residues of NS4A (Val-23‘ to Leu-31‘)ii The prime symbol (`) is used to distinguish between NS4A residues and NS3 residues of (no prime). are essential for activating NS3 upon NS3/4A protease complex formation. This study aims to design new specific allosteric NS3/4A protease inhibitors by mutating Val-23‘, Ile-25‘, and Ile-29‘ into bulkier amino acids. Pep-15, a synthetic peptide, showed higher binding affinity towards HCV-NS3 subtype-4 than native NS4A. The Kd of Pep-15 (80.0 ± 8.0 nM) was twice as high as that of native NS4A (169 ± 37 nM). The mutant Pep-15 inhibited the catalytic activity of HCV-NS3 by forming an inactive complex. Molecular dynamics simulations suggested that a cascade of conformational changes occurred, especially in the catalytic triad arrangements, thereby inactivating NS3. A large shift in the position of Ser-139 was observed, leading to loss of critical hydrogen bonding with His-57. Even though this study is not a classic drug discovery study—nor do we propose Pep-15 as a drug candidate—it serves as a stepping stone towards developing a potent inhibitor of hitherto untargeted HCV subtypes.

【 授权许可】

Unknown