title: The HEPT Analogue WPR-6 Is Active against a Broad Spectrum of Nonnucleoside Reverse Transcriptase Drug-Resistant HIV-1 Strains of Different Serotypes.
abstract: Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are important components of the highly active antiretroviral therapy (HAART) used to treat human immunodeficiency type 1 virus (HIV-1). However, because of the emergence of drug resistance and the adverse effects of current anti-HIV drugs, it is essential to develop novel NNRTIs with an excellent safety profile, improved activity against NNRTI-resistant viruses, and enhanced activity against clinical isolates of different subtypes. Here, we have identified 1-[(benzyloxy)methyl]-6-(3,5-dimethylbenzyl)-5-iodopyrimidine-2,4(1H,3H)-dione (WPR-6), a novel NNRTI with a 50% effective concentration (EC50) of 2 to 4 nM against laboratory-adapted HIV-1 strain SF33 and an EC50 of 7 to 14 nM against nucleoside reverse transcriptase inhibitor-resistant HIV-1 strain 7391 with a therapeutic index of >1 × 10(4). A panel of five representative clinical virus isolates of different subtypes circulating predominantly in China was highly sensitive to WPR-6, with EC50s ranging from 1 to 6 nM. In addition, WPR-6 showed excellent antiviral potency against the most prevalent NNRTI-resistant viruses containing the K103N and Y181C mutations. To determine whether WPR-6 selects for novel resistant mutants, in vitro resistance selection was conducted with laboratory-adapted HIV-1 strain SF33 on MT-4 cells. The results demonstrated that V106I and Y188L were the two dominant NNRTI-associated resistance mutations detected in the breakthrough viruses. Taken together, these in vitro data indicate that WPR-6 has greater efficacy than the reference HEPT analogue TNK651 and the marketed drug nevirapine against HIV-1. However, to develop it as a new NNRTI, further improvement of its pharmacological properties is warranted.
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
authors.forename: Weisi
authors.initials: W
authors.lastname: Xu
authors.affiliation: School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: Jianxiong
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Beijing You'an Hospital, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Sun
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Yin
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Jiao
authors.affiliation: School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: Junyi
authors.initials: J
authors.lastname: Liu
authors.affiliation: Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, USA Key Laboratory of Medical Molecular Virology of MOE/MOH and Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Shao
authors.affiliation: School of Pharmaceutical Sciences, Peking University, Beijing, China mal@chinaaids.cn xiaoweiwang@bjmu.edu.cn.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China mal@chinaaids.cn xiaoweiwang@bjmu.edu.cn.
authors.forename: Liying
authors.initials: L
authors.lastname: Ma
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D002681:China; D024882:Drug Resistance, Viral / Q000187:drug effects*; D015658:HIV Infections / Q000188:drug therapy; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests / Q000379:methods; D009154:Mutation / Q000187:drug effects; D019829:Nevirapine / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D065288:Serogroup
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase