2. Academic Validation
  3. Lead optimization to improve the antiviral potency of 2-aminobenzamide derivatives targeting HIV-1 Vif-A3G axis

Lead optimization to improve the antiviral potency of 2-aminobenzamide derivatives targeting HIV-1 Vif-A3G axis

  • Eur J Med Chem. 2021 Nov 15:224:113680. doi: 10.1016/j.ejmech.2021.113680.
Xinxin Zhong 1,  Ronghua Luo 2,  Guoyi Yan 3,  Kai Ran 1,  Huifang Shan 1,  Jie Yang 1,  Yuanyuan Liu 1,  Su Yu 1,  Chunlan Pu 1,  Yongtang Zheng 4,  Rui Li 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, PR China.
  • 2 Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology,Chinese Academy of Sciences, Kunming, Yunnan, 650223, PR China.
  • 3 School of Pharmacy, Henan University, Kaifeng, Henan, 475001, PR China.
  • 4 Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology,Chinese Academy of Sciences, Kunming, Yunnan, 650223, PR China. Electronic address: Zhengyt@mail.kiz.ac.cn.
  • 5 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, PR China. Electronic address: lirui@scu.edu.cn.
PMID: 34245947 DOI: 10.1016/j.ejmech.2021.113680
Abstract

The viral infectivity factor (Vif)-apolipoprotein B mRNA-editing Enzyme, catalytic polypeptide-like 3G (APOBEC3G) axis has been recognized as a valid target for developing novel small-molecule therapies for acquired immune deficiency syndrome (AIDS) or for enhancing innate immunity against viruses. Our previous work reported the novel Vif antagonist 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)sulfonyl)benzamide (2) with strong Antiviral activity. In this work, through optimizations of ring C of 2, we discovered the more potent compound 6m with an EC50 of 0.07 μM in non-permissive H9 cells, reflecting an approximately 5-fold enhancement of Antiviral activity compared to that of 2. Western blotting indicated that 6m more strongly suppressed the defensive protein Vif than 2 at the same concentration. Furthermore, 6m suppressed the replication of various clinical drug-resistant HIV strains (FI, NRTI, NNRTI, IN and PI) with relatively high efficacy. These results suggested that compound 6m is a more potent candidate for treating AIDS.

Keywords

Antiviral activity; Vif antagonists; Vif mediated A3G degradation.

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