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Potential HIV Drug Keeps Virus out of Cells: "PIE12-trimer is an entry-inhibitor, has the potential to work as a microbicide to prevent people from contracting HIV and as a treatment for HIV infected people." published study pdf attached
 
 
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"Our studies indicate that PIE12-trimer is a promising entry inhibitor that could overcome limitations associated with the two currently approved entry inhibitors, Fuzeon (high dosing, susceptibility to resistance) and Selzentry/maraviroc (only effective against R5 viruses), and may also prove to have a better resistance profile than even the newest class of HIV-1 inhibitors. In addition to a possible therapeutic agent, PIE12-trimer is an ideal candidate for a topical microbicide, as its protease resistance would allow it to withstand the protease- rich environment of the vaginal mucosa. In the absence of a safe and effective HIVvaccine, a topical microbicide to prevent the sexual transmission of HIV is an urgent unmet global health need. The ultimate utility of PIE12-trimer as a microbicide or therapeutic agent will be determined by advanced pre-clinical and clinical studies, including characterization of pharmacokinetics, in vivo toxicity, effectiveness in animal models of HIV infection (alone or in combination with other HIV inhibitors), andoptimization of formulations for microbicide gels or vaginal rings."
 
ScienceDaily (Aug. 24, 2010) - Following up a pioneering 2007 proof-of-concept study, a University of Utah biochemist and colleagues have developed a promising new anti-HIV drug candidate, PIE12-trimer, that prevents HIV from attacking human cells.
 
Michael S. Kay, M.D., Ph.D., associate professor of biochemistry in the University of Utah School of Medicine and senior author of the study published on Aug. 18, 2010, online by the Journal of Virology, is raising funds to begin animal safety studies, followed by human clinical trials in two to three years. Kay believes PIE12-trimer is ideally suited for use as a vaginal microbicide (topically applied drug) to prevent HIV infection. His research group is particularly focused on preventing the spread of HIV in Africa, which has an estimated two-thirds of the world's 33 million HIV patients according to the World Health Organization.
 
"We believe that PIE12-trimer could provide a major new weapon in the arsenal against HIV/AIDS. Because of its ability to block the virus from infecting new cells, PIE12-trimer has the potential to work as a microbicide to prevent people from contracting HIV and as a treatment for HIV infected people. HIV can develop resistance rapidly to existing drugs, so there is a constant need to develop new drugs in hopes of staying ahead of the virus." Kay said.
 
PIE12-trimer was designed with a unique "resistance capacitor" that provides it with a strong defense against the emergence of drug-resistant viruses.
 
Peptide drugs have great therapeutic potential, but are often hampered by their rapid degradation in the body. D-peptides are mirror-image versions of natural peptides that cannot be broken down, potentially leading to higher potency and longevity in the body. Despite these potential advantages, no D-peptides have yet been developed.
 
PIE12-trimer consists of three D-peptides (PIE12) linked together that block a "pocket" on the surface of HIV critical for HIV's gaining entry into the cell. "Clinical trials will determine if PIE12-trimer is as effective in humans as it is in the lab," Kay said.
 
Across the world, HIV occurs in many different strains and has the ability to mutate to resist drugs aimed at stopping it. Due to the high conservation of the pocket region across strains, PIE12-trimer worked against all major HIV strains worldwide, from Southeast Asia and South America to the United States and Africa.
 
To help advance toward human clinical trials, Kay and co-authors Brett D. Welch, Ph.D., and Debra M. Eckert, Ph.D., research assistant professor of biochemistry, formed a company, Kayak Biosciences, which is owned by the University of Utah Research Foundation. If PIE12-trimer proves to be an effective and safe drug against HIV, the same D-Peptide drug design principles can be applied against other viruses, according to Kay. Approval of the first D-peptide drug would also greatly stimulate development of other D-peptide drugs.
 
The study's first authors are Welch, and U of U graduate student J. Nicholas Francis. Also contributing were U graduate students Joseph Redman and Matthew Weinstock, as well as Eckert. Images of how PIE12 binds to the HIV pocket were obtained using X-ray crystallography, a technology that provides high-resolution analysis of atomic structures, and were provided by Frank Whitby, Ph.D., research assistant professor of biochemistry, and Christopher P. Hill, Ph.D., professor and co-chair of the Department of Biochemistry. The study includes colleagues from Thomas Jefferson University in Philadelphia and Monogram Biosciences, South San Francisco, Calif.
 
This research was funded by the National Institutes of Health and the University of Utah Research Foundation.
 
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Design of a Potent D-peptide HIV-1 Entry Inhibitor with a Strong Barrier to Resistance - published pdf attached
 
JVI published online ahead of print on 18 August 2010
 
Brett D. Welch1, J. Nicholas Francis1, Joseph S. Redman1, Suparna Paul2, Matthew T. Weinstock1, Jacqueline D. Reeves3, Yolanda S. Lie3, Frank G. Whitby1, Debra M. Eckert1, Christopher P. Hill1, Michael J. Root2, and Michael S. Kay1* From 1Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah 84112, 2Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, and 3Monogram Biosciences, 345 Oyster Point Blvd, South San Francisco, CA 94080.
 
Abstract
 
The HIV gp41 N-trimer "pocket" region is an ideal viral target because it is extracellular, highly conserved, and essential for viral entry. Here, we report the design of a pocket-specific D-peptide, PIE12-trimer, that is extraordinarily elusive to resistance and characterize its inhibitory and structural properties. D-peptides (peptides composed of D-amino acids) are promising therapeutic agents due to their insensitivity to protease degradation. PIE12-trimer was designed using structure-guided mirror-image phage display and linker optimization and is the first D-peptide HIV entry inhibitor with the breadth and potency required for clinical use. PIE12-trimer has ultra-high affinity for the gp41 pocket, providing it with a reserve of binding energy ("resistance capacitor") that yields a dramatically improved resistance profile compared to other fusion inhibitors. These results demonstrate that the gp41 pocket is an ideal drug target and establish PIE12-trimer as a leading HIV antiviral candidate.
 
Discussion
 
PIE12-trimer is a D-peptide entry inhibitor with ~80-fold enhanced potency and an estimated >100,000-fold improved binding affinity compared to the best previously reported D-peptide. This dramatic improvement in affinity produces excellent breadth and a charged resistance capacitor to combat the emergence of resistance mutations. Indeed, PIE12-trimer was able to withstand the impact of resistance mutations to earlier generation D-peptides and required a much longer selection (65 weeks) to generate resistant stains. Ongoing work is exploring the mechanism of PIE7-dimer, PIE12-dimer, and PIE12-trimer resistance and its relationship to group O's insensitivity. A key question is whether HIV can develop resistance against these inhibitors independent of changes in affinity (e.g., kinetics) that are capable of maintaining viral fitness. Viral escape affects even the newest class of FDA-approved HIV-1 drugs, integrase inhibitors. Resistance to raltegravir and corresponding treatment failure was observed in a significant subset of patients in both the Phase II and III clinical studies (5), and corresponding resistance mutations can be seen within 4 weeks when selected in viral passaging studies (28). Our studies indicate that PIE12-trimer is a promising entry inhibitor that could overcome limitations associated with the two currently approved entry inhibitors, Fuzeon (high dosing, susceptibility to resistance) and Selzentry/maraviroc (only effective against R5 viruses), and may also prove to have a better resistance profile than even the newest class of HIV-1 inhibitors. In addition to a possible therapeutic agent, PIE12-trimer is an ideal candidate for a topical microbicide, as its protease resistance would allow it to withstand the protease- rich environment of the vaginal mucosa. In the absence of a safe and effective HIV vaccine, a topical microbicide to prevent the sexual transmission of HIV is an urgent unmet global health need. The ultimate utility of PIE12-trimer as a microbicide or therapeutic agent will be determined by advanced pre-clinical and clinical studies, including characterization of pharmacokinetics, in vivo toxicity, effectiveness in animal models of HIV infection (alone or in combination with other HIV inhibitors), and optimization of formulations for microbicide gels or vaginal rings. More generally, this work unequivocally shows that D-peptide inhibitors can be designed with high potency and specificity against natural L-protein targets. The D- peptide design methodology described here can be applied to diverse biomedical applications, particularly for the many viruses that share HIV's hairpin-closing entry mechanism (e.g., influenza, Ebola, RSV, SARS, Dengue, and West Nile viruses). Our resistance capacitor design strategy may also be generally applicable for treating other rapidly evolving diseases, especially when combined with recent advances in anticipating likely structural sources of drug resistance (37). Finally, the development of PIE12-trimer as a strong clinical candidate will allow D-peptide therapeutics to be evaluated in vivo to determine if their theoretical advantages warrant a prominent role as a new class of therapeutic agents.
 
 
 
 
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