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Polyethylene Glycol 40-Modified Peptide with High Therapeutic Efficacy in Simian-Human Immunodeficiency Virus-Acutely Infected Rhesus Monkeys.
- Source :
-
Journal of virology [J Virol] 2020 Jul 01; Vol. 94 (14). Date of Electronic Publication: 2020 Jul 01 (Print Publication: 2020). - Publication Year :
- 2020
-
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 ( t <subscript>1/2</subscript> ; 10.39 h in rats), which compensated for decreased in vitro activity (50% effective concentration [EC <subscript>50</subscript> ] 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.<br /> (Copyright © 2020 American Society for Microbiology.)
- Subjects :
- Animals
Humans
Macaca mulatta
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
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
Subjects
Details
- Language :
- English
- ISSN :
- 1098-5514
- Volume :
- 94
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Journal of virology
- Publication Type :
- Academic Journal
- Accession number :
- 32404523
- Full Text :
- https://doi.org/10.1128/JVI.00386-20