Tan, Wan Chein and Othman, Shatrah and Lim, See Khai and Rashid, Nurshamimi Nor and Heh, Choon-Han (2022) A reverse structure-based design of HPV E7 inhibitor. Current Computer-Aided Drug Design, 18 (4). pp. 318-325. ISSN 1573-4099, DOI https://doi.org/10.2174/1573409918666220509214449.
Full text not available from this repository.Abstract
Human papillomavirus (HPV) is a small, non-enveloped double-stranded circular DNA virus. The high-risk types of HPV are claimed to be responsible for over 99% of cervical cancers. One of the essential HPV oncoproteins, E7, is responsible for escaping from G1/S cell cycle arrest in HPV-infected cells by binding to the retinoblastoma protein (pRb) through its LXCXE binding site. Objective: To design a peptide inhibitor targeting HPV E7 through an in silico approach. Methods: In this study, the LXCXE binding domain of pRb is used as a target to design peptide inhibitors using a reverse structure-based approach. The designed amino acid sequence from the B pocket of pRb, named peptide Y, was further investigated in vitro analysis. The cytotoxicity of the peptide was analysed in two cell lines, namely, CaSki, containing an integrated HPV16 genome, and HaCaT, an immortalized keratinocyte cell. Cell cycle analysis was also carried out in both cell lines treated with peptides. Results: In the in silico approach, a 9-amino acids peptide sequence formed 4 conventional hydrogen bonds with LXCXE motif was selected for in vitro assay. Based on the cytotoxicity analysis, the peptide showed low toxicity in both cell lines, where the cell viability remained over 74% when treated with peptide Y. The peptide also caused an accumulation of cells in G0/G1 (+5.4%) and S phase (+10.2%) and a reduction of cells in the G2/M phase (-14.9%) in the CaSki cells with no significant effect on normal cells, indicating it is a potential HPV inhibitor. Conclusion: A peptide inhibitor, peptide Y, that was designed from the LXCXE binding motif in pRb can inhibit HPV E7 by causing a cell accumulation effect in G0/G1, and S phases of the cell cycle in the HPV transformed cell lines. These findings could contribute to HPV E7 peptide inhibitor in the future.
| Item Type: | Article |
|---|---|
| Funders: | Ministry of Higher Education under the Fundamental Research Grant Scheme (FRGS) [FP015-2016] |
| Uncontrolled Keywords: | Human Papillomavirus E7; pRb; Peptide inhibitor; LXCXE; Cell cycle; In silico |
| Subjects: | R Medicine R Medicine > RM Therapeutics. Pharmacology |
| Divisions: | Faculty of Medicine |
| Depositing User: | Ms. Juhaida Abd Rahim |
| Date Deposited: | 30 Aug 2023 02:49 |
| Last Modified: | 30 Aug 2023 02:49 |
| URI: | http://eprints.um.edu.my/id/eprint/41019 |
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