Stapled SC34EK fusion inhibitors with high potency against HIV-1and improved protease resistance

HIV fusion inhibitors are promising therapeutic agents for AIDS treatment. One fusion inhibitor has been approved as anti-HIV drug, while more of them are in preclinical studies or clinical trials. Highly active fusion inhibitors with excellent pharmacokinetic properties are still needed for development of anti-HIV drugs. We found that all-hydrocarbon staples inserted in SC34 EK could not only enhance the inhibitory activity of inhibitors against HIV-1, but also improve protease resistance. Further study revealed that SC34 EK-1 containing a staple was a potent fusion inhibitor with IC;value of 0.04-6.4 nmol/L towards diverse HIV-1 subtypes and half-life value of 112 min against protease hydrolysis. X-ray crystallography studies indicated that introduction of a hydrocarbon staple in SC34 EK could make the amino acid at the interaction surface form perfect conformation to promote inhibitor peptide interacting with target.

HIV fusion inhibitors are promising therapeutic agents for AIDS treatment. One fusion inhibitor has been approved as anti-HIV drug, while more of them are in preclinical studies or clinical trials. Highly active fusion inhibitors with excellent pharmacokinetic properties are still needed for development of anti-HIV drugs. We found that all-hydrocarbon staples inserted in SC34 EK could not only enhance the inhibitory activity of inhibitors against HIV-1, but also improve protease resistance. Further study revealed that SC34 EK-1 containing a staple was a potent fusion inhibitor with IC_(50) value of 0.04-6.4 nmol/L towards diverse HIV-1 subtypes and half-life value of 112 min against protease hydrolysis. X-ray crystallography studies indicated that introduction of a hydrocarbon staple in SC34 EK could make the amino acid at the interaction surface form perfect conformation to promote inhibitor peptide interacting with target.