1H-imidazole-2,5-dicarboxamides as ns4a peptidomimetics: Identification of a new approach to inhibit hcv-ns3 protease
AuthorsOmar, Abdelsattar M.
Elfaky, Mahmoud A.
Arold, Stefan T.
Soror, Sameh H.
Khayat, Maan T.
Asfour, Hani Z.
Bamane, Faida H.
El-Araby, Moustafa E.
KAUST DepartmentBiological and Environmental Sciences and Engineering (BESE) Division
Computational Bioscience Research Center (CBRC)
Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
Structural Biology and Engineering
Permanent link to this recordhttp://hdl.handle.net/10754/662444
MetadataShow full item record
AbstractThe nonstructural (NS) protein NS3/4A protease is a critical factor for hepatitis C virus (HCV) maturation that requires activation by NS4A. Synthetic peptide mutants of NS4A were found to inhibit NS3 function. The bridging from peptide inhibitors to heterocyclic peptidomimetics of NS4A has not been considered in the literature and, therefore, we decided to explore this strategy for developing a new class of NS3 inhibitors. In this report, a structure-based design approach was used to convert the bound form of NS4A into 1H-imidazole-2,5-dicarboxamide derivatives as first generation peptidomimetics. This scaffold mimics the buried amino acid sequence Ile-25‘ to Arg-28‘ at the core of NS4A21‘–33‘ needed to activate the NS3 protease. Some of the synthesized compounds (Coded MOC) were able to compete with and displace NS4A21‘–33‘ for binding to NS3. For instance, N5-(4-guanidinobutyl)-N2-(n-hexyl)-1H-imidazole-2,5-dicarboxamide (MOC-24) inhibited the binding of NS4A21‘–33‘ with a competition half maximal inhibitory concentration (IC50) of 1.9 ± 0.12 µM in a fluorescence anisotropy assay and stabilized the denaturation of NS3 by increasing the aggregation temperature (40% compared to NS4A21‘–33‘). MOC-24 also inhibited NS3 protease activity in a fluorometric assay. Molecular dynamics simulations were conducted to rationalize the differences in structure–activity relationship (SAR) between the active MOC-24 and the inactive MOC-26. Our data show that MOC compounds are possibly the first examples of NS4A peptidomimetics that have demonstrated promising activities against NS3 proteins.
CitationOmar, A. M., Elfaky, M. A., Arold, S. T., Soror, S. H., Khayat, M. T., Asfour, H. Z., … El-Araby, M. E. (2020). 1H-Imidazole-2,5-Dicarboxamides as NS4A Peptidomimetics: Identification of a New Approach to Inhibit HCV-NS3 Protease. Biomolecules, 10(3), 479. doi:10.3390/biom10030479
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 research reported in this publication was also supported by funding from King Abdullah University of Science and Technology (KAUST). The authors acknowledge, with thanks, the Science and Technology Unit, King Abdulaziz University for technical support. Authors are exceptionally grateful to MDPI, the Editor Ms. Sophia Lin, and the respected reviewers for being very cooperative to publish this manuscript, considering the current circumstances of the COVID-19 pandemic that hindered us from covering some reviewers’ comments.
- Establishment of an in vitro assay system for screening hepatitis C virus protease inhibitors using high performance liquid chromatography.
- Authors: Sudo K, Inoue H, Shimizu Y, Yamaji K, Konno K, Shigeta S, Kaneko T, Yokota T, Shimotohno K
- Issue date: 1996 Aug
- Virus-specific cofactor requirement and chimeric hepatitis C virus/GB virus B nonstructural protein 3.
- Authors: Butkiewicz N, Yao N, Zhong W, Wright-Minogue J, Ingravallo P, Zhang R, Durkin J, Standring DN, Baroudy BM, Sangar DV, Lemon SM, Lau JY, Hong Z
- Issue date: 2000 May
- Enzymatic characterization of membrane-associated hepatitis C virus NS3-4A heterocomplex serine protease activity expressed in human cells.
- Authors: Hamill P, Jean F
- Issue date: 2005 May 3
- Macrocyclic Hepatitis C Virus NS3/4A Protease Inhibitors: An Overview of Medicinal Chemistry.
- Authors: Pillaiyar T, Namasivayam V, Manickam M
- Issue date: 2016
- The design of a potent inhibitor of the hepatitis C virus NS3 protease: BILN 2061--from the NMR tube to the clinic.
- Authors: Tsantrizos YS
- Issue date: 2004