US researchers have developed new peptides that might be more efficient in preventing HIV than other drugs of the same class.
"Our 'D-peptides' offer several potential therapeutic advantages over existing peptide entry inhibitors, which are costly, require high dose injections, and suffer from the emergence of drug-resistance," said University of Utah biochemist Michael S. Kay.
"In contrast, our D-peptides resist degradation, so they have the potential to be administered by mouth and last longer in the bloodstream. Since these inhibitors have a unique inhibitory mechanism, they should work well in combination with existing HIV inhibitors," he added.
Previous studies have already identified this essential structure as a promising drug target, using protein structures determined at the National Synchrotron Light Source (NSLS) at the U.S. Department of Energy's Brookhaven National Laboratory. However, several earlier attempts to target this pocket failed to produce potent and non-toxic pocket-specific entry inhibitors.
In the current study, the researchers used a high-throughput technique to screen a "library" containing hundreds of millions of peptides to identify the rare peptides, which would bind to the pocket structure and inhibit HIV entry.
Thereafter, the researchers analysed the structure of the most promising candidate peptides, using x-ray crystallography at the NSLS. They looked into how an extremely bright beam of x-rays, available only at synchrotron sources, bounces off and is refracted by the sample to determine the positions of individual atoms.
"These structures reveal details of how the peptides bind and guide the development of future inhibitors," said paper co-author Annie Heroux, a biologist and crystallography specialist at Brookhaven Lab.
This structure-assisted design led to the discovery of D-peptides with up to a 40,000-fold improved antiviral potency over previously reported D-peptides. The structures also suggest ways to engineer the peptides to reduce the chance of drug resistance.