Synthetic bulky NS4A peptide variants bind to and inhibit HCV NS3 protease
AuthorsEl-Araby, Moustafa E.
Omar, Abdelsattar M.
Soror, Sameh H.
Arold, Stefan T.
Khayat, Maan T.
Asfour, Hani Z.
Elfaky, Mahmoud A.
KAUST DepartmentBiological and Environmental Science and Engineering (BESE) Division
Computational Bioscience Research Center (CBRC)
Structural Biology and Engineering
Permanent link to this recordhttp://hdl.handle.net/10754/667611
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AbstractNS4A 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‘)i 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.
CitationEl-Araby, M. E., Omar, A. M., Soror, S. H., Arold, S. T., Khayat, M. T., Asfour, H. Z., … Elfaky, M. A. (2020). Synthetic bulky NS4A peptide variants bind to and inhibit HCV NS3 protease. Journal of Advanced Research, 24, 251–259. doi:10.1016/j.jare.2020.01.003
SponsorsThis project was funded by the National Plan for Science, Technology and Innovation (MAARIFAH), King Abdulaziz City for Science and Technology, the Kingdom of Saudi Arabia; Award number 12-BIO3193-03. The authors also, acknowledge with thanks Science and Technology Unit, King Abdulaziz University for technical support. The research by STA reported in this publication was supported by funding from King Abdullah University of Science and Technology (KAUST). The authors have declared no conflict of interest.
JournalJournal of Advanced Research
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