title: An effective conjugation strategy for designing short peptide-based HIV-1 fusion inhibitors.
abstract: Lengthy peptides corresponding to the C-terminal heptad repeat (C-peptides) of human immunodeficiency virus type 1 (HIV-1) gp41 are potent inhibitors against virus-cell fusion. Designing short C-peptide-based HIV-1 fusion inhibitors could potentially redress the physicochemical and technical liabilities of a long-peptide therapeutic. However, designing such inhibitors with high potency has been challenging. We generated a conjugated architecture by incorporating small-molecule inhibitors of gp41 into the N-terminus of a panel of truncated C-peptides. Among these small molecule-capped short peptides, the 26-residue peptide Indole-T26 inhibited HIV-1 Env-mediated cell-cell fusion and viral replication at low nanomolar levels, reaching the potency of the only clinically used 36-residue peptide T20 (enfuvirtide). Collectively, our work opens up a new avenue for developing short peptide-based HIV-1 fusion inhibitors, and may have broad applicability to the development of modulators of other class I fusion proteins.
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing, 100850, China. keliangliu55@126.com chaow301@gmail.com.
authors.forename: Guodong
authors.initials: G
authors.lastname: Liang
authors.affiliation: School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China.
authors.forename: Huixin
authors.initials: H
authors.lastname: Wang
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens and AIDS Research Center, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 9, Dong Dan San Tiao, Beijing 100730, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Chong
authors.affiliation: School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China.
authors.forename: Siqi
authors.initials: S
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing, 100850, China. keliangliu55@126.com chaow301@gmail.com.
authors.forename: Xifeng
authors.initials: X
authors.lastname: Jiang
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens and AIDS Research Center, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 9, Dong Dan San Tiao, Beijing 100730, China.
authors.forename: Yuxian
authors.initials: Y
authors.lastname: He
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing, 100850, China. keliangliu55@126.com chaow301@gmail.com.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing, 100850, China. keliangliu55@126.com chaow301@gmail.com.
authors.forename: Keliang
authors.initials: K
authors.lastname: Liu
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D015195:Drug Design; D015700:HIV Envelope Protein gp41 / Q000737:chemistry; D023581:HIV Fusion Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010455:Peptides