New Inhibitor Is More Potent Blocking HIV From Entering Human Cells
University of Utah School of Medicine researchers have discovered a peptide 40,000 times more potent at preventing HIV from entering human cells than any previously reported agent in the same class of inhibitors.
The discovery of this peptide offers hope for developing new drugs to prevent and treat AIDS, the researchers report in a study published this week in the Proceedings of the National Academy of Sciences online.
"We are quite excited by the therapeutic potential of these peptides," said Michael S. Kay, M.D., Ph.D., assistant professor of biochemistry and the study's senior author. "Our next steps are pre-clinical and clinical trials to see if their promise in the laboratory translates to a safe and effective drug in humans."
Peptides are natural and artificial compounds, such as hormones and antibiotics, that play many biological roles. The researchers screened billions of peptides before discovering D-peptides, according to Brett Welch, a University of Utah graduate student and the study's first author. "We screened candidate peptides for those that bound most tightly to an essential structure in HIV called 'the pocket'," Welch said. "This pocket is a key component of HIV's cell entry machinery and is a very promising drug target."
The researchers are particularly excited by the possibility of using these inhibitors as microbicides-topically applied drugs that prevent the spread of HIV infection. A widely used, potent, and cost-effective microbicide would save millions of lives in the developing world, according to Kay.
"An effective HIV vaccine will be the ultimate solution to the AIDS epidemic, but such a vaccine may not be available for many years," he said. "We are also seeking industrial partners to develop our D-peptides as a treatment for patients already infected with HIV."
D-peptides, are mirror images of naturally occurring peptides, analogous to left and right hands. But unlike natural peptides, which the body easily absorbs, D-peptides have the potential to remain in the body for longer periods.
"D-peptides are not found in nature, so the body is unable to digest them. As a result, they are much more durable than natural peptides and have the potential to be taken by mouth," Kay said. "Natural peptides generally make poor drugs because they must be injected and are readily degraded by the body."
The study includes high-resolution structural analysis, using X-ray crystallography to reveal the atomic details of how D-peptides bind to the HIV pocket. This will guide the development of further improved inhibitors. The structures were obtained by collaborators Christopher P. Hill, Ph.D., University of Utah professor of biochemistry; Andrew VanDemark, Ph.D., formerly at Utah and now an assistant professor at the University of Pittsburgh; as well as Anne Heroux, Ph.D, at the National Synchrotron Light Source at Brookhaven National Lab.
The study also addresses one of the most serious challenges in developing new HIV therapies--the rapid emergence of drug resistance. HIV mutates quickly and can adapt to resist the inhibitory effects of a previously effective drug. "A key feature of the current work is our attempt to anticipate and avoid drug resistance," Kay said. "The HIV pocket is similar in all HIV strains and cannot mutate without disrupting HIV's ability to enter cells."
The authors also introduce the idea of a "resistance capacitor," which stores reserve energy in the inhibitor to combat possible resistance mutations.
Looking ahead to possible medical applications, Kay said, "The field of D-peptide design is in its infancy, but we hope these studies will stimulate the development of D-peptide therapeutics for other viruses that enter cells using a similar mechanism to HIV, such as Ebola and Influenza."