(Press-News.org) Researchers from Munich and Naples have shown that minimal modification of a synthetic peptide with anti-HIV activity results in a new compound with more than two orders of magnitude higher binding affinity to the chemokine receptor CXCR4 and greatly improved anti-HIV activity. This could be a step toward the design of new, more effective drugs against AIDS, inflammatory diseases, and some forms of cancer.
Different strains of HIV-1 use either the chemokine receptor CCR5 or CXCR4 for entry into immune cells. While drugs that block usage of CCR5 by the virus are already available for anti-HIV therapy, no drugs have been approved that prevent the virus from using the CXCR4 receptor. Because the new cyclic peptide may be used to block CXCR4, it is a promising new drug candidate to block HIV-1 infections.
An international, interdisciplinary team including researchers in pharmaceutical radiochemistry and chemistry at the Technische Universität München (TUM), a group of molecular modelers at the University of Naples, and virologists at the Helmholtz Zentrum München reported the results in Angewandte Chemie International Edition. This work was initiated by the radiochemists and organic chemists at TUM, who realized that their approach to modifying peptides as high-affinity CXCR4 ligands for imaging of cancers also has the potential to open a whole new area of drug research.
The researchers used a smart trick to augment both the binding affinity and the anti-HIV activity of an already known lead structure: They shifted one of the important side chains from the carbon to a neighboring nitrogen, thus fixing the skeleton of the molecule to present its binding groups in an improved orientation.
The cyclic structure of the peptide, with one unnatural D-amino acid (the mirror image of the natural amino acid tyrosine) and one so-called "peptoid" structure, makes the compound stable against enzymatic degradation and thus suitable for in vivo applications. Since CXCR4 receptors also play an important role in cancer metastasis, derivatives of this compound are also being tested as new agents for imaging and treatment of cancer. The team's "frozen peptoid" displays a 400 to 1500 times higher binding affinity to the CXCR4 ligand compared to other CXCR4-targeting compounds currently under clinical development, including one already involved in the treatment of non-Hodgkin lymphoma and multiple myeloma.
"We are very happy that the specific modifications designed by our team have led to a drug compound that may be useful for treatment of multiple life-threatening diseases," says Prof. Horst Kessler, a senior fellow of the TUM Institute for Advanced Study and "emeritus of excellence" in the TUM Department of Chemistry. "For anti-HIV therapy," adds Prof. Ruth Brack-Werner, a virologist from the Helmholtz Zentrum, "the new compound may provide a drug against particularly aggressive HIV-1 strains that come up in HIV-infected individuals after many years of infection." "We look forward with great enthusiasm to the next preclinical and clinical tests," says Prof. Hans-Jürgen Wester, TUM Chair of Pharmaceutical Radiochemistry. "These compounds offer exciting possibilities."
This research was supported by the Excellence Initiative of the German federal and state governments (TUM-IAS, Center of Integrated Protein Research Munich), the German Research Foundation (DFG SFB 824, Subproject B5), and the Helmholtz Zentrum München, Chemical Biology Intitiative.
A Conformationally Frozen Peptoid Boosts CXCR4 Affinity and Anti-HIV Activity. Oliver Demmer, Andreas O. Frank, Franz Hagn, Margret Schottelius, Luciana Marinelli, Sandro Cosconati, Ruth Brack-Werner, Stephan Kremb, Hans-Jürgen Wester, and Horst Kessler. Angewandte Chemie Int. Ed., 2012, 51, 8110-8113.
Prof. Dr. Horst Kessler
Technische Universität München
TUM-IAS at the Department of Chemistry
85747 Garching, Germany
Tel.: +49 89 289 13300
Fax.: +49 89 289 13210
Technische Universitaet Muenchen (TUM) is one of Europe's leading universities. It has roughly 480 professors, 9000 academic and non-academic staff, and 31,000 students. It focuses on the engineering sciences, natural sciences, life sciences, medicine, and economic sciences. After winning numerous awards, it was selected as an "Elite University" in 2006 and 2012 by the Science Council (Wissenschaftsrat) and the German Research Foundation (DFG). The university's global network includes an outpost with a research campus in Singapore. TUM is dedicated to the ideal of a top-level research-based entrepreneurial university. http://www.tum.de
Technische Universitaet Muenchen
Potential drug molecule shows enhanced anti-HIV activity
Small change locks molecule into shape, yields major effect
ELSE PRESS RELEASES FROM THIS DATE:
PITTSBURGH—Pine trees are one of the biggest contributors to air pollution. They give off gases that react with airborne chemicals – many of which are produced by human activity – creating tiny, invisible particles that muddy the air. New research from a team led by Carnegie Mellon University's Neil Donahue shows that the biogenic particles formed from pine tree emissions are much more chemically interesting and dynamic than previously thought. The study provides the first experimental evidence that such compounds are chemically transformed by free radicals, the same compounds ...
During the Neolithic Age (approximately 10000 BCE), early man evolved from hunter-gatherer to farmer and agriculturalist, living in larger, permanent settlements with a variety of domesticated animals and plant life. This transition brought about significant changes in terms of the economy, architecture, man's relationship to the environment, and more. Now Dr. Ran Barkai of Tel Aviv University's Department of Archaeology and Ancient Near Eastern Civilizations has shed new light on this milestone in human evolution, demonstrating a direct connection between the development ...
PROVIDENCE, R.I. – A Rhode Island Hospital researcher has found that the majority of bariatric surgery patients being treated for obesity have clinically significant obstructive sleep apnea (OSA), but report fewer symptoms than other sleep disorders patients. The study by Katherine M. Sharkey, M.D., Ph.D., of the department of medicine, division of pulmonary, critical care and sleep medicine at Rhode Island Hospital, and University Medicine, is published online in advance of print in the journal Sleep and Breathing. "Patients with obstructive sleep apnea frequently complain ...
ARLINGTON, VA, August 9, 2012—The Journal of the Pediatric Infectious Diseases Society (JPIDS) today released the largest and most rigorous evaluation to date of the impact on reducing the days of antibiotic therapy in a children's hospital using a prospective-audit-with-feedback antibiotic stewardship program (ASP). The study utilized a control group of the 25-member children's hospitals of the Child Health Corporation of America. A companion article describes how the ASP was created within this 317-bed tertiary care children's hospital and clinicians' attitudes toward ...
This press release is available in German.Energy storage systems are one of the key technologies for the energy turnaround. With their help, the fluctuating supply of electricity based on photovoltaics and wind power can be stored until the time of consumption. At Karlsruhe Institute of Technology (KIT), several pilot plants of solar cells, small wind power plants, lithium-ion batteries, and power electronics are under construction to demonstrate how load peaks in the grid can be balanced and what regenerative power supply by an isolated network may look like in the future. "High-performance ...
Scientists at Tulane University School of Medicine, led by Dr. James Antoon and Dr. Barbara Beckman, have characterized two drugs targeting sphingosine kinase (SK), an enzyme involved in cancer growth and metastasis. New treatments specifically attacking cancer cells, but not normal ones, are critical in the fight against cancer. The results, which appear in the July 2012 issue of Experimental Biology and Medicine, demonstrate the role of SK in drug resistance and therapeutic potential of SK inhibitors. "Sphingosine kinase is a relatively new molecular target," says ...
New Rochelle, NY, August 9, 2012—Women comprise nearly half of the HIV-infected population worldwide, but these 15.5 million women tend to be under-represented in clinical trials of anti-HIV drug therapies. The U.S. Food and Drug Administration (FDA) has created a database from 40 clinical studies to assess gender differences in the efficacy of antiretroviral treatments. The results of this study are presented in an article in AIDS Patient Care and STDs, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers. The article is available free on the AIDS Patient Care ...
Researchers have successfully tested a vaccine for the deadly Nipah virus in monkeys, raising hopes that it could provide similar protection for humans. With greater than a 75 percent fatality rate and the ability to be transmitted directly from person to person, Nipah has long been a significant concern for infectious-disease experts. The virus, which is carried naturally by fruit bats, was first discovered in Malaysia in 1998. Outbreaks have occurred in nearly every year since, in Singapore, Bangladesh and India. "This vaccine is based on a protein from Hendra virus, ...
VIDEO: How would you like to experience the effects of running three miles or staving off Type 2 diabetes without making drastic changes in your lifestyle? With nutrition supplements developed by... Click here for more information. How would you like to experience the effects of running three miles or staving off type two diabetes without making drastic changes in your lifestyle? With nutrition supplements developed by a professor at the University of Tennessee, Knoxville, ...
SALINA, KAN. -- The type of relationship a woman has with her ex-partner is a factor in how the couple shares custody of children, according to a Kansas State University expert on postdivorce and co-parenting relationships. In a study of divorced or separated mothers sharing physical custody of their children with their former partners, Mindy Markham, assistant professor of family studies and human services on the university's Salina campus, identified three patterns of co-parenting -- continuously contentious, always amicable and bad to better -- as well as negative ...