title: A novel bispecific peptide HIV-1 fusion inhibitor targeting the N-terminal heptad repeat and fusion peptide domains in gp41.
abstract: HIV-1 fusion with the target cell is initiated by the insertion of the gp41 fusion peptide (FP) into the target cell membrane and the interaction between the gp41 N- and C-terminal heptad repeats (NHR and CHR), followed by the formation of the six-helix bundle (6-HB) fusion core. Therefore, both FP and NHR are important targets for HIV-1 fusion inhibitors. Here, we designed and synthesized a dual-target peptidic HIV-1 fusion inhibitor, 4HR-LBD-VIRIP, in which 4HR-LBD is able to bind to the gp41 NHR domain, while VIRIP is able to interact with gp41 FP. We found that 4HR-LBD-VIRIP is about tenfold more potent than 4HR-LBD and VIRIP in inhibiting HIV-1IIIBinfection and HIV-1 envelope glycoprotein (Env)-mediated cell-cell fusion, suggesting that this dual-target HIV-1 fusion inhibitor possesses a strong synergistic antiviral effect. A biophysical analysis indicates that 4HR-LBD-VIRIP can interact with N70 peptide that contains the gp41 NHR and FP domains and binds with lipid membrane. This study provides a new approach for designing novel viral fusion inhibitors against HIV and other enveloped viruses with class I membrane fusion proteins.
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Pharmaceutical Chemistry, Beijing, 100850, China.
authors.forename: Xifeng
authors.initials: X
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Pharmaceutical Chemistry, Beijing, 100850, China.
authors.forename: Qiyan
authors.initials: Q
authors.lastname: Jia
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Basic Medical College, Fudan University, Shanghai, 200032, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Basic Medical College, Fudan University, Shanghai, 200032, China.|Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, 10065, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Yu
authors.affiliation: Department of Chemistry, Tsinghua University, Beijing, 100084, China.
authors.forename: Jishen
authors.initials: J
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Pharmaceutical Chemistry, Beijing, 100850, China.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Pharmaceutical Chemistry, Beijing, 100850, China.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Cai
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Basic Medical College, Fudan University, Shanghai, 200032, China. shibojiang@fudan.edu.cn.|Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, 10065, USA. shibojiang@fudan.edu.cn.
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Pharmaceutical Chemistry, Beijing, 100850, China. keliangliu55@126.com.
authors.forename: Keliang
authors.initials: K
authors.lastname: Liu
mesh_terms: D000595:Amino Acid Sequence / Q000187:drug effects; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000235:genetics*; D023581:HIV Fusion Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D015497:HIV-1 / Q000737:chemistry / Q000187:drug effects / Q000472:pathogenicity; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics*; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D000072417:Protein Domains
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D010455:Peptides
keywords: HIV-1; Peptide fusion inhibitor; Synergistic effect; gp41