Contemporary Medicinal Chemistry Strategies for the Discovery and Development of Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors

J Med Chem. 2022 Mar 10;65(5):3729-3757. doi: 10.1021/acs.jmedchem.1c01758.

Zhao Wang ¹, Srinivasulu Cherukupalli ¹, Minghui Xie ¹, Wenbo Wang ¹, Xiangyi Jiang ¹, Ruifang Jia ¹, Christophe Pannecouque ², Erik De Clercq ², Dongwei Kang ¹ ³, Peng Zhan ¹ ³, Xinyong Liu ¹ ³

Affiliations

1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, P.R. China.
2 Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, 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, 44 West Culture Road, 250012 Jinan, Shandong, P.R. China.

PMID: 35175760 DOI: 10.1021/acs.jmedchem.1c01758

Abstract

Currently, HIV-1 non-nucleoside Reverse Transcriptase inhibitors (NNRTIs) are a major component of the highly active anti-retroviral therapy (HAART) regimen. However, the occurrence of drug-resistant strains and adverse reactions after long-term usage have inevitably compromised the clinical application of NNRTIs. Therefore, the development of novel inhibitors with distinct anti-resistance profiles and better pharmacological properties is still an enormous challenge. Herein, we summarize state-of-the-art medicinal chemistry strategies for the discovery of potent NNRTIs, such as structure-based design strategies, contemporary computer-aided drug design, covalent-binding strategies, and the application of multi-target-directed ligands. The strategies described here will facilitate the identification of promising HIV-1 NNRTIs.

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