A PEG40 Modified Peptide with High Therapeutic Efficacy in SHIV Acute Infected Rhesus Monkeys.

: Anti-human immunodeficiency virus (HIV)-1 fusion peptides have been studied for nearly two decades but few candidates have found useful clinical applications. One reason underlying the failure of such agents to reach the clinic is their poor pharmacokinetic properties, and many efforts have been made to overcome this problem. In this study, we modified C34, a peptide inhibitor of HIV-1 fusion, at its conserved glycosylation site using polyethylene glycols (PEGs) of different molecular weights. PEG40-NC, a conjugate of C34 and branched PEG 40 kDa, which has been previously shown to improve the pharmacokinetic profiles of proteins, showed a significantly extended half-life (t1/2 = 10.39 h in rats), which compensated for decreased in vitro activity (EC50 = 18.51 nM). PEG40-NC also showed a similar mechanism of action to that of C34. PEG40-NC monotherapy in acutely SHIV infected rhesus monkeys significantly suppressed viral load compared with a control treatment. Efficacy was linked to the extended half-life and lymphatic exposure conferred by attached PEG40. These results highlight the potential of further clinical investigations of PEG40-NC in combination with antiretroviral therapy or other anti-HIV agents.IMPORTANCE The poor pharmacokinetics severely hindered the clinical use of anti-HIV peptides. Different small molecules, such as lipid, cholesterol and small PEG were designed to modify peptides to improve their pharmacokinetics. Here we incorporated large branched PEG to anti-HIV peptide and obtained a conjugate with extended half-life and improved in vivo efficacy. The strategy we developed here can also be applicable for the development of other peptide candidates.