Analysis Affinity and Kinetics of HR2/gp41 (HIV-1) with PEG-like Polymers by KinExA (CAT#: STEM-MB-0064-CJ)

Introduction

Therapeutic peptides and proteins are essential in modern medicine due to their high specificity and efficacy against biological targets. The main strategy to improve the stability and circulating life of peptide/protein therapeutics is the synthesis of hydrophilic polymers such as polyethylene glycol (PEG) through covalent linkages. PEG conjugation (or polyethylene glycolization) provides a physical barrier to proteolytic enzymes and increases the hydrodynamic volume of peptide/protein therapeutics, thereby reducing protein hydrolysis and renal elimination, respectively. A class of peptide drugs that have shown therapeutic value are fusion inhibitors that block type 1 HIV (HIV-1) infection. These peptides are derived from the heptapeptide repeat 1 (HR1) and heptapeptide repeat 2 (HR2) structural domains of the HIV-1 glycoprotein gp41.7 - 12 In mediating viral entry into target cells, the HR1 and HR2 structural domains from the three gp41s bind in a hairpin trimer conformation, bringing the virus and cell membrane into close proximity for membrane fusion. Fusion inhibitors from these structural domains disrupt the formation of hairpin trimers in a dominant-negative manner, thereby preventing HIV-1 from entering the host cell during the primary phase of infection before viral RNA is integrated into the host cell genome. While the effect of polyethylene glycolisation on the efficacy of anti-fusion has been determined, the details of the inhibition process and the impact on the inhibition of binding affinity and kinetics have yet to be determined. Answering these key questions will provide valuable insights into the underlying peptide-mediated inhibition process - polymer couples against HIV-1 membrane fusion - and may have broad implications for the judicious design and application of countless polymer couples against other enveloped viruses that infect cells by similar mechanisms.