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Article

Covalently Targeted Highly Conserved Tyr318 to Improve the Drug Resistance Profiles of HIV-1 NNRTIs: A Proof-of-Concept Study

by
Zhenzhen Zhou
1,
Bairu Meng
1,
Jiaqi An
1,
Fabao Zhao
1,
Yanying Sun
1,
Dan Zeng
1,
Wenna Wang
1,
Shenghua Gao
1,
Yu Xia
1,
Caiyun Dun
1,
Erik De Clercq
2,
Christophe Pannecouque
2,
Peng Zhan
1,3,
Dongwei Kang
1,3,* and
Xinyong Liu
1,3,*
1
Key Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, Jinan 250012, China
2
Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, K.U. Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000 Leuven, Belgium
3
China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, Shandong University, 44 West Culture Road, Jinan 250012, China
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2023, 24(2), 1215; https://doi.org/10.3390/ijms24021215
Submission received: 3 November 2022 / Revised: 15 December 2022 / Accepted: 4 January 2023 / Published: 7 January 2023
(This article belongs to the Special Issue Antiviral Drug Discovery)
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Abstract

This study presents proof of concept for designing a novel HIV-1 covalent inhibitor targeting the highly conserved Tyr318 in the HIV-1 non-nucleoside reverse transcriptase inhibitors binding pocket to improve the drug resistance profiles. The target inhibitor ZA-2 with a fluorosulfate warhead in the structure was found to be a potent inhibitor (EC50 = 11–246 nM) against HIV-1 IIIB and a panel of NNRTIs-resistant strains, being far superior to those of NVP and EFV. Moreover, ZA-2 was demonstrated with lower cytotoxicity (CC50 = 125 µM). In the reverse transcriptase inhibitory assay, ZA-2 exhibited an IC50 value of 0.057 µM with the ELISA method, and the MALDI-TOF MS data demonstrated the covalent binding mode of ZA-2 with the enzyme. Additionally, the molecular simulations have also demonstrated that compounds can form covalent binding to the Tyr318.
Keywords: HIV-1; NNRTIs; DAPYs; covalent inhibitors; drug resistance HIV-1; NNRTIs; DAPYs; covalent inhibitors; drug resistance

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MDPI and ACS Style

Zhou, Z.; Meng, B.; An, J.; Zhao, F.; Sun, Y.; Zeng, D.; Wang, W.; Gao, S.; Xia, Y.; Dun, C.; et al. Covalently Targeted Highly Conserved Tyr318 to Improve the Drug Resistance Profiles of HIV-1 NNRTIs: A Proof-of-Concept Study. Int. J. Mol. Sci. 2023, 24, 1215. https://doi.org/10.3390/ijms24021215

AMA Style

Zhou Z, Meng B, An J, Zhao F, Sun Y, Zeng D, Wang W, Gao S, Xia Y, Dun C, et al. Covalently Targeted Highly Conserved Tyr318 to Improve the Drug Resistance Profiles of HIV-1 NNRTIs: A Proof-of-Concept Study. International Journal of Molecular Sciences. 2023; 24(2):1215. https://doi.org/10.3390/ijms24021215

Chicago/Turabian Style

Zhou, Zhenzhen, Bairu Meng, Jiaqi An, Fabao Zhao, Yanying Sun, Dan Zeng, Wenna Wang, Shenghua Gao, Yu Xia, Caiyun Dun, and et al. 2023. "Covalently Targeted Highly Conserved Tyr318 to Improve the Drug Resistance Profiles of HIV-1 NNRTIs: A Proof-of-Concept Study" International Journal of Molecular Sciences 24, no. 2: 1215. https://doi.org/10.3390/ijms24021215

APA Style

Zhou, Z., Meng, B., An, J., Zhao, F., Sun, Y., Zeng, D., Wang, W., Gao, S., Xia, Y., Dun, C., De Clercq, E., Pannecouque, C., Zhan, P., Kang, D., & Liu, X. (2023). Covalently Targeted Highly Conserved Tyr318 to Improve the Drug Resistance Profiles of HIV-1 NNRTIs: A Proof-of-Concept Study. International Journal of Molecular Sciences, 24(2), 1215. https://doi.org/10.3390/ijms24021215

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