Improvement of the HIV fusion inhibitor C34 activity by membrane anchoring and enhanced exposure.

AUGUSTO, MT; HOLLMANN A; CASTANHO MA; PESSI A; SANTOS NC

Lisboa

Congreso; 9th European Biophysics Congress; 2013

EBSA

It was recently demonstrated that the combination of cholesterol-tagging, by using a PEG moiety as spacer and dimerization of the C34 peptide sequence, resulted in an increase of the antiviral potency and in an extension of the in vivo half-life of these HIV fusion inhibitors, named HIVP3 (C34-PEG4-cholesterol) and HIVP4 ([C34-PEG4]2-cholesterol). The aim of the present work was to evaluate the interaction of these molecules with membrane model systems and human blood cells. Membrane partition, dipole potential and pressure assays indicate that HIVP3 and HIVP4 interact preferentially with cholesterol-rich liquid ordered membranes mimicking biological membranes microdomains, known as lipid rafts. Interaction of peptides with human erythrocytes and peripheral blood mononuclear cells (PBMC) showed that HIVP3 and HIVP4 are able to interact with the membrane of both blood cells in the same extension as another C34 derivate, C34-cholesterol. However, the pocket binding domain (PBD) of both new C34 derivates seems to be more exposed to the aqueous environment than on C34-cholesterol. All this data indicate that the synergic effect between a membranotropic behavior and an enhanced exposure of PBD of the inhibitors result in a more efficient blocking of HIV entry.