title: A Lipopeptide HIV-1/2 Fusion Inhibitor with Highly PotentIn Vitro,Ex Vivo, andIn VivoAntiviral Activity.
abstract: Peptides derived from the C-terminal heptad repeat (CHR) region of the human immunodeficiency virus type 1 (HIV-1) fusogenic protein gp41 are potent viral entry inhibitors, and currently, enfuvirtide (T-20) is the only one approved for clinical use; however, emerging drug resistance largely limits its efficacy. In this study, we generated a novel lipopeptide inhibitor, named LP-19, by integrating multiple design strategies, including an N-terminal M-T hook structure, an HIV-2 sequence, intrahelical salt bridges, and a membrane-anchoring lipid tail. LP-19 showed stable binding affinity and highly potent, broad, and long-lasting antiviral activity. Inin vitrostudies, LP-19 efficiently inhibited HIV-1-, HIV-2-, and simian immunodeficiency virus (SIV)-mediated cell fusion, viral entry, and infection, and it was highly active against diverse subtypes of primary HIV-1 isolates and inhibitor-resistant mutants.Ex vivostudies demonstrated that LP-19 exhibited dramatically increased anti-HIV activity and an extended half-life in rhesus macaques. In short-term monotherapy, LP-19 reduced viral loads to undetectable levels in acutely and chronically simian-human immunodeficiency virus (SHIV)-infected monkeys. Therefore, this study offers an ideal HIV-1/2 fusion inhibitor for clinical development and emphasizes the importance of the viral fusion step as a drug target.IMPORTANCEThe peptide drug T-20 is the only viral fusion inhibitor in the clinic, which is used for combination therapy of HIV-1 infection; however, it requires a high dosage and easily induces drug resistance, calling for a new drug with significantly improved pharmaceutical profiles. Here, we have developed a short-lipopeptide-based fusion inhibitor, termed LP-19, which mainly targets the conserved gp41 pocket site and shows highly potent inhibitory activity against HIV-1, HIV-2, and even SIV isolates. LP-19 exhibits dramatically increased antiviral activity and an extended half-life in rhesus macaques, and it has potent therapeutic efficacy in SHIV-infected monkeys, highlighting its high potential as a new viral fusion inhibitor for clinical use.
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.|Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Chong
authors.affiliation: Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.|Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xue
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.|Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Shengwen
authors.initials: S
authors.lastname: Xiong
authors.affiliation: Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.|Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Cong
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.|Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Ding
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.|Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Yuanmei
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.|Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Zixuan
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.|Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Chen
authors.affiliation: Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.|Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Beijing Institute of Microbiology and Epidemiology, Beijing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: He
authors.affiliation: Beijing Institute of Microbiology and Epidemiology, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.|Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wei
authors.affiliation: Beijing Institute of Microbiology and Epidemiology, Beijing, China.
authors.forename: Yusen
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China qinchuan@pumc.edu.cn yhe@ipbcams.ac.cn.|Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Qin
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China qinchuan@pumc.edu.cn yhe@ipbcams.ac.cn.|Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Yuxian
authors.initials: Y
authors.lastname: He
mesh_terms: D000818:Animals; D015195:Drug Design; D055808:Drug Discovery; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D023581:HIV Fusion Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000187:drug effects*; D015498:HIV-2 / Q000187:drug effects* / Q000502:physiology; D006207:Half-Life; D006801:Humans; D055666:Lipopeptides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D008253:Macaca mulatta; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects* / Q000502:physiology; D019562:Viral Load / Q000187:drug effects; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D055666:Lipopeptides; D010446:Peptide Fragments; C514787:gp41 protein, Human immunodeficiency virus 1; D000077560:Enfuvirtide
keywords: HIV-1; HIV-2; fusion inhibitor; lipopeptide