Polyethylene Glycol 40-Modified Peptide with High Therapeutic Efficacy in Simian-Human Immunodeficiency Virus-Acutely Infected Rhesus Monkeys

J Virol. 2020 Jul 1;94(14):e00386-20. doi: 10.1128/JVI.00386-20. Print 2020 Jul 1.

Abstract

Anti-human immunodeficiency virus type 1 (anti-HIV-1) fusion peptides have been studied for nearly 2 decades, but few candidates have found useful clinical applications. One factor 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 (PEG40), 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 (50% effective concentration [EC50] of 18.51 nM). PEG40-NC also showed a mechanism of action similar to that of C34. PEG40-NC monotherapy in acutely simian-human immunodeficiency virus (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 Poor pharmacokinetics have 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. In this study, 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 in this study can also be applicable for the development of other peptide candidates.

Keywords: HIV inhibitor discovery; anti-HIV fusion peptide; peptide therapeutics chemical modification to extend half-life; pharmacokinetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • HIV Envelope Protein gp41* / chemistry
  • HIV Envelope Protein gp41* / pharmacokinetics
  • HIV Envelope Protein gp41* / pharmacology
  • HIV Fusion Inhibitors* / chemistry
  • HIV Fusion Inhibitors* / pharmacokinetics
  • HIV Fusion Inhibitors* / pharmacology
  • HIV Infections* / drug therapy
  • HIV Infections* / metabolism
  • HIV Infections* / pathology
  • HIV-1 / metabolism*
  • Humans
  • Macaca mulatta
  • Peptide Fragments* / chemistry
  • Peptide Fragments* / pharmacokinetics
  • Peptide Fragments* / pharmacology
  • Polyethylene Glycols / chemistry*
  • Simian Acquired Immunodeficiency Syndrome* / drug therapy
  • Simian Acquired Immunodeficiency Syndrome* / metabolism
  • Simian Acquired Immunodeficiency Syndrome* / pathology
  • Simian Immunodeficiency Virus / metabolism*

Substances

  • HIV Envelope Protein gp41
  • HIV Fusion Inhibitors
  • Peptide Fragments
  • peptide C34
  • Polyethylene Glycols