Utah researchers discover a new class of highly potent HIV inhibitors.
HIV infection starts when the virus forcibly enters a vulnerable human cell, ultimately leading to AIDS. Agents that prevent this entry process are promising new agents for the prevention and treatment of AIDS.
In a paper being published online in the Proceedings of the National Academy of Sciences this week, scientists at the University of Utah School of Medicine report the discovery of a new class of highly potent inhibitors of HIV entry called "D-peptides".
The authors report the design of an HIV entry inhibitor that is 40,000-fold more potent than the best previously reported inhibitors in this class. "These D-peptides were initially discovered by screening billions of candidate peptides for those that bound most tightly to an essential structure in HIV called 'the pocket'. This pocket is a key component of HIV's cell entry machinery and is a very promising drug target" said Brett Welch, the senior graduate student who spearheaded the study.
"We are particularly excited by the possibility of using these inhibitors as microbicides - topically applied drugs that prevent the spread of HIV infection" said Prof. Michael Kay, who directed the study. He added: "If widely used, a potent and cost-effective microbicide would save millions of lives in the developing world. An effective HIV vaccine will be the ultimate solution to the AIDS epidemic, but such a vaccine may not be available for many years. We have also applied for patent protection with the U. of Utah Technology Commercialization Office and are 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. Dr. Kay said: "Our studies on D-peptides allow us to explore a parallel universe of peptide structures that nature has not been able to access during evolution. D-peptides are not found in nature, so the body is unable to digest them. As a result, D-peptides are much more durable than natural peptides and have the potential to be taken by mouth and last in the body for an extended period of time, unlike natural peptides, which are generally poor drugs since they must be injected and are readily degraded by the body".
The study also includes high-resolution structural analysis using x-ray crystallography that reveals the atomic details of how the D-peptides bind to the HIV pocket and will guide the development of further improved inhibitors. The structures were obtained by University of Utah collaborators Prof. Chris Hill and Dr. Andrew VanDemark (now an Assistant Professor at U. of Pittsburgh), as well as Dr. Anne Heroux at the National Synchrotron Light Source at Brookhaven National Lab.
One of most serious challenges in developing new HIV therapies is the rapid emergence of drug resistance. HIV mutates at a rapid rate and can often 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. The HIV pocket is very similar in all HIV strains and cannot mutate without disrupting HIV's ability to enter cells." said Dr. Kay. The authors also introduce the idea of a "resistance capacitor" that stores reserve energy in the inhibitor to combat possible resistance mutations.
Looking ahead to possible medical applications, Dr. Kay said "The field of D-peptide design is in its infancy, but we hope that 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. We are quite excited by the therapeutic potential of these peptides, and 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."
This research was funded by the National Institutes of Health, the University of Utah Research Foundation, and the American Cancer Society.