TAR RNA selective targeting ruthenium(II) complexes as HIV-1 reverse transcriptase inhibitors: On exploring structure-activity relationships of multiple positions.

Autor: Liu M; Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research & Development of Natural Products, School of Pharmacy, Yunnan University, Kunming 650050, PR China., Xie DD; Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research & Development of Natural Products, School of Pharmacy, Yunnan University, Kunming 650050, PR China., Guo YX; Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research & Development of Natural Products, School of Pharmacy, Yunnan University, Kunming 650050, PR China., Zhao RY; Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research & Development of Natural Products, School of Pharmacy, Yunnan University, Kunming 650050, PR China., Liu FD; Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research & Development of Natural Products, School of Pharmacy, Yunnan University, Kunming 650050, PR China., Zhang H; Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research & Development of Natural Products, School of Pharmacy, Yunnan University, Kunming 650050, PR China., Gao F; Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research & Development of Natural Products, School of Pharmacy, Yunnan University, Kunming 650050, PR China. Electronic address: gaofeng@ynu.edu.cn.
Jazyk: angličtina
Zdroj: Journal of inorganic biochemistry [J Inorg Biochem] 2024 Oct; Vol. 259, pp. 112664. Date of Electronic Publication: 2024 Jul 15.
DOI: 10.1016/j.jinorgbio.2024.112664
Abstrakt: HIV-1 reverse transcriptase (RT) inhibitors play a crucial role in the treatment of HIV by preventing the activity of the enzyme responsible for the replication of the virus. The HIV-1 Tat protein binds to transactivation response (TAR) RNA and recruits host factors to stimulate HIV-1 transcription. We have created a small library consisting of 4 × 6 polypyridyl Ru(II) complexes that selectively bind to TAR RNA, with targeting groups specific to HIV-1 TAR RNA. The molecule design was conducted by introducing hydroxyl or methoxy groups into an established potent TAR binder. The potential TAR binding ability was analysis from nature charge population and electrostatic potential by quantum chemistry calculations. Key modifications were found to be R 1 and R 3 groups. The most potent and selective TAR RNA binder was a3 with R 1  = OH, R 2  = H and R 3  = Me. Through molecular recognition of hydrogen bonds and electrostatic attraction, they were able to firmly and selectively bind HIV-1 TAR RNA. Furthermore, they efficiently obstructed the contact between TAR RNA and Tat protein, and inhibited the reverse transcription activity of HIV-1 RT. The polypyridyl Ru(II) complexes were chemical and photo-stable, and sensitive and selective spectroscopic responses to TAR RNA. They exhibited little toxicity towards normal cells. Hence, this study might offer significant drug design approaches for researching AIDS and other illnesses associated with RT, including HCV, EBOV, and SARS-CoV-2. Moreover, it could contribute to fundamental research on the interactions of inorganic transition metal complexes with biomolecules.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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