title: Enfuvirtide-PEG conjugate: A potent HIV fusion inhibitor with improved pharmacokinetic properties.
abstract: Enfuvirtide (ENF) is a clinically used peptide drug for the treatment of HIV infections, but its poor pharmacokinetic profile (T1/2 = 1.5 h in rats) and low aqueous solubility make the therapy expensive and inconvenience. In this study, we present a simple and practical strategy to address these problems by conjugating ENF with polyethylene glycol (PEG). Site-specific attachment of a 2 kDa PEG at the N-terminus of ENF resulted in an ENF-PEG (EP) conjugate with high solubility (≥3 mg/mL) and long half-life in rats (T1/2 = 16.1 h). This conjugate showed similar antiviral activity to ENF against various primary HIV-1 isolates (EC50 = 6-91 nM). Mechanistic studies suggested the sources of the antiviral potency. The conjugate bound to a functional domain of the HIV gp41 protein in a helical conformation with high affinity (Kd = 307 nM), thereby inhibiting the gp41-mediated fusion of viral and host-cell membranes. As PEG conjugation has advanced many bioactive proteins and peptides into clinical applications, the EP conjugate described here represents a potential new treatment for HIV infections that may address the unmet medical needs associated with the current ENF therapy.
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China; National Engineering Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022, China.
authors.forename: Shuihong
authors.initials: S
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Infection Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Chinese Center of Disease Control and Prevention, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Changping District, Beijing 102206, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China; University of Chinese Academy of Sciences, Shijingshan District, Beijing 100049, China.
authors.forename: Zhenxing
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China.
authors.forename: Xun
authors.initials: X
authors.lastname: Lv
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China; Center for Influenza Research and Early-warning, Chinese Academy of Sciences (CASCIRE), Chaoyang District, Beijing 100101, China.
authors.forename: George F
authors.initials: GF
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Infection Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Chinese Center of Disease Control and Prevention, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Changping District, Beijing 102206, China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Shao
authors.affiliation: State Key Laboratory of Infection Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Chinese Center of Disease Control and Prevention, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Changping District, Beijing 102206, China. Electronic address: mal@chinaaids.cn.
authors.forename: Liying
authors.initials: L
authors.lastname: Ma
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China; National Engineering Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022, China; Center for Influenza Research and Early-warning, Chinese Academy of Sciences (CASCIRE), Chaoyang District, Beijing 100101, China. Electronic address: lixb@im.ac.cn.
authors.forename: Xuebing
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000493:pharmacokinetics*; D023581:HIV Fusion Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics*; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects; D006207:Half-Life; D010446:Peptide Fragments / Q000737:chemistry / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D012995:Solubility
chemical_list: D000998:Antiviral Agents; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D000077560:Enfuvirtide; D011092:Polyethylene Glycols
keywords: Conjugation; Enfuvirtide; Fusion inhibitor; Human immunodeficiency virus; Pharmacokinetics; Poly(ethylene glycol)