title: Glycosylated enfuvirtide: a long-lasting glycopeptide with potent anti-HIV activity.
abstract: Many peptide-based therapeutics have short circulatory half-lives. We report here that the pharmacokinetics of an anti-HIV peptide drug enfuvirtide (ENF) can be dramatically improved by a chemical glycosylation approach. A set of glycosylated ENFs with varying glycosylation sites and glycan structures were synthesized. Among these, a sialic acid-introduced peptide (SL-ENF) demonstrated a 15-fold extended half-life in rats relative to ENF (T1/2: 23.1 vs 1.5 h), and its antiviral potency was comparable to that of ENF (EC50: 2 vs 3 nM). SL-ENF bound to a functional fragment of the HIV fusogenic protein gp41 and formed complexes with high affinity and α-helicity, revealing the mechanism behind its potent antiviral activity. Because it is widely accepted in biology that glycosylation protects proteins from denaturation and proteases, our approach may be useful for the development of novel protein and peptide drugs with enhanced pharmaceutical properties.
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences , Chaoyang District, Beijing 100101, China.
authors.forename: Shuihong
authors.initials: S
authors.lastname: Cheng
authors.forename: Xuesong
authors.initials: X
authors.lastname: Chang
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: George F
authors.initials: GF
authors.lastname: Gao
authors.forename: Yiming
authors.initials: Y
authors.lastname: Shao
authors.forename: Liying
authors.initials: L
authors.lastname: Ma
authors.forename: Xuebing
authors.initials: X
authors.lastname: Li
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000077560:Enfuvirtide; D006020:Glycopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006031:Glycosylation; D006678:HIV / Q000187:drug effects*; D015700:HIV Envelope Protein gp41 / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D006020:Glycopeptides; D015700:HIV Envelope Protein gp41; D010446:Peptide Fragments; D000077560:Enfuvirtide