Enfuvirtide-PEG conjugate: A potent HIV fusion inhibitor with improved pharmacokinetic properties.

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Enfuvirtide-PEG conjugate: A potent HIV fusion inhibitor with improved pharmacokinetic properties.

Eur J Med Chem. 2016 Oct 04;121:232-7

Authors: Cheng S, Wang Y, Zhang Z, Lv X, Gao GF, Shao Y, Ma L, Li X

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.

PMID: 27240277 [PubMed - indexed for MEDLINE]

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