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Manypeptide-based therapeutics have short circulatory half-lives.We report here that the pharmacokinetics of an anti-HIV peptide drugenfuvirtide (ENF) can be dramatically improved by a chemical glycosylationapproach. A set of glycosylated ENFs with varying glycosylation sitesand glycan structures were synthesized. Among these, a sialic acid-introducedpeptide (SL-ENF) demonstrated a 15-fold extended half-life in ratsrelative 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 fusogenicprotein gp41 and formed complexes with high affinity and α-helicity,revealing the mechanism behind its potent antiviral activity. Becauseit is widely accepted in biology that glycosylation protects proteinsfrom denaturation and proteases, our approach may be useful for thedevelopment of novel protein and peptide drugs with enhanced pharmaceuticalproperties. [ABSTRACT FROM AUTHOR]