The use of hairpin DNA duplexes as HIV-1 fusion inhibitors: Synthesis, characterization, and activity evaluation

•A new category of hairpin DNA duplex-based HIV-1 entry inhibitors was reported.•These molecules showed anti-HIV-1 activity at low μM concentrations.•These molecules all possessed high thermal stability.•They interacted with the primary pocket in the gp41 N-terminal heptad repeat.

Discovery of new drugs for the treatment of AIDS that possess unique structures associated with novel mechanisms of action are of great importance due the rapidity with which drug-resistant HIV-1 strains evolve. Recently we reported on a novel class of DNA duplex-based HIV-1 fusion inhibitors modified with hydrophobic groups. The present study describes a new category of hairpin fusion inhibitor DNA duplexes bearing a 3 nucleotide loop located at either the hydrophobic or hydrophilic end. The new loop structures were designed to link 2 separate duplex-forming oligodeoxynucleotides (ODNs) to make helix-assembly easier and more thermally stable resulting in a more compact form of DNA duplex based HIV-1 fusion inhibitors. A series of new hairpin duplexes were tested for anti-HIV-1 cell–cell membrane fusion activity. In addition, Tm, CD, fluorescent resonance energy transfer assays, and molecular modeling analyses were carried out to define their structural activity relationships and possible mechanisms of action.

Graphical abstractA new class of hairpin DNA duplex-based HIV-1 entry inhibitors was presented in this report. These molecules showed anti-HIV-1 activity at low μM concentrations and all possessed high terminal stability.Figure optionsDownload full-size imageDownload as PowerPoint slide