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

Enfuvirtide-PEG conjugate: A potent HIV fusion inhibitor with improved pharmacokinetic properties.
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Cheng S, Wang Y, Zhang Z, Lv X, Gao GF, Shao Y, Ma L, Li X,


Cheng S, Wang Y, Zhang Z, Lv X, Gao GF, Shao Y, Ma L, Li X, (click to view)

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

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European journal of medicinal chemistry 2016 05 13121() 232-7 doi 10.1016/j.ejmech.2016.05.027

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.

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