Development of potent and long-acting HIV-1 fusion inhibitors

T20 (enfuvirtide) is the first approved HIV entry inhibitor and currently the only viral fusion inhibitor, but its low efficacy and genetic barrier to resistance significantly limit its application, calling for a next-generation drug.On the basis of the M-T hook structure, we recently developed a short-peptide named HP23, which mainly targets the deep pocket site of gp41 and possesses highly potent antiviral activity. To improve the pharmaceutical properties of a peptide-based inhibitor, we modified HP23 by different classes of lipids including fatty acid, cholesterol, and sphingolipids. To avoid the potential problem of oxidation, the methionine residue in the M-T hook sequence of HP23 was replaced with leucine.Peptides were synthesized and their anti-HIV activity and biophysical properties were determined.A group of lipopeptides were generated with greatly improved anti-HIV activity. Promisingly, a fatty acid-conjugated lipopeptide named LP-11 showed potent and broad inhibitory activity against diverse primary HIV-1 isolates and clinically drug-resistant mutants, and it had dramatically increased ex-vivo antiviral activity and extended half-life. Also, LP-11 displayed highly enhanced α-helicity and thermal stability, and it was physically stable under high temperature and humidity.LP-11 has high potentials for clinical development and it can serve as an ideal tool for exploring the mechanisms of HIV-1 fusion and inhibition.