Abstract
Enfuvirtide and T-1249 are two HIV-1 fusion inhibitor peptides that bind to gp41 and prevent its fusogenic conformation, inhibiting viral entry into host cells. Previous studies established the relative preferences of these peptides for membrane model systems of defined lipid compositions. We aimed to understand the interaction of these peptides with the membranes of erythrocytes and peripheral blood mononuclear cells. The peptide behavior toward cell membranes was followed by di-8-ANEPPS fluorescence, a lipophilic probe sensitive to the changes in membrane dipole potential. We observed a fusion inhibitor concentration-dependent decrease on the membrane dipole potential. Quantitative analysis showed that T-1249 has an approximately eight-fold higher affinity towards cells, when compared with enfuvirtide. We also compared the binding towards di-8-ANEPPS labeled lipid vesicles that model cell membranes and obtained concordant results. We demonstrated the distinct enfuvirtide and T-1249 membranotropism for circulating blood cells, which can be translated to a feasible in vivo scenario. The enhanced interaction of T-1249 with cell membranes correlates with its higher efficacy, as it can increase and accelerate the drug binding to gp41 in its pre-fusion state.
Highlights
The Human Immunodeficiency Virus type 1 (HIV-1) is a highly pathogenic, evasive and difficult to eradicate agent that causes Acquired Immunodeficiency Syndrome (AIDS)
Isolated human erythrocytes and PBMC membranes were successfully labeled with di-8-ANEPPS
Designing peptide drugs based in gp41 sequence to prevent viral entry into host cells has been in focus in the antiretroviral research field
Summary
The Human Immunodeficiency Virus type 1 (HIV-1) is a highly pathogenic, evasive and difficult to eradicate agent that causes Acquired Immunodeficiency Syndrome (AIDS). This discovery in the early 1980s triggered major international scientific efforts in antiviral drug discovery and development [1]. This engagement triggers the exposure of the hydrophobic N-terminal region of another envelope glycoprotein, gp41 This fusion peptide anchors to the membrane of the host cell, enabling the two gp helical heptad repeat domains, the Cterminal (CHR or HR2) and the N-terminal (NHR or HR1), to fold into each other to form a hairpin-like structure (6-helix bundle). This approximates the cell and the viral membranes, facilitating their fusion and the release of the viral content into the cell [3]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
