title: Development of benzimidazole derivatives to inhibit HIV-1 replication through protecting APOBEC3G protein.
abstract: Human APOBEC3G (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G, A3G) is a potent restriction factor against human immunodeficiency virus type 1 (HIV-1) by inducing hypermutation of G to A in viral genome after its incorporation into virions. HIV-1 Vif (Virion Infectivity Factor) counteracts A3G by inducing ubiquitination and proteasomal degradation of A3G protein. Vif-A3G axis therefore is a promising therapeutic target of HIV-1. Here we report the screening, synthesis and SAR studies of benzimidazole derivatives as potent inhibitors against HIV-1 replication via protecting A3G protein. Based on the steep SAR of the benzimidazole scaffold, we identified compound 14 and 26 which provided the best potency, with IC50 values of 3.45 nM and 58.03 nM respectively in the anti-HIV-1 replication assay in H9 cells. Compound 14 and 26 also afforded protective effects on A3G protein level. Both compounds have been proved to be safe in acute toxicological studies. Taken together, we suggest that these two benzimidazole derivatives can be further developed as a new category of anti-HIV-1 leads.
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China; Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Pan
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China; Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
authors.forename: Xin
authors.initials: X
authors.lastname: He
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Chen
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China; Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
authors.forename: Guannan
authors.initials: G
authors.lastname: Geng
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China; Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
authors.forename: Haihua
authors.initials: H
authors.lastname: Luo
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China; Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. Electronic address: zhangh92@mail.sysu.edu.cn.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China; Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. Electronic address: baichuan@mail.sysu.edu.cn.
authors.forename: Chuan
authors.initials: C
authors.lastname: Bai
mesh_terms: D000071480:APOBEC-3G Deaminase; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D003564:Cytidine Deaminase / Q000378:metabolism*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D016346:Gene Products, vif / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology*; D057166:High-Throughput Screening Assays; D006801:Humans; D008297:Male; D051379:Mice; D059748:Proteolysis / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D001562:Benzimidazoles; D016346:Gene Products, vif; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase
keywords: APOBEC3G; Benzimidazole; HIV-1; Vif