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Syrrx Researchers Report Atomic Structure of Human HSD-1, an Important Target for the Potential Treatment of Diabetes

Posted on: Friday, 5 November 2004, 06:00 CST

Syrrx Inc., a next generation structure-based drug discovery company, today reported the publication of the atomic structure of human 11(beta)-hydroxysteroid dehydrogenase type-1 (HSD-1). HSD-1 inhibitors are being investigated in clinical trials for the potential treatment of type II diabetes.

Studies to date indicate that HSD-1 helps regulate levels of cortisol, a steroid hormone that plays an important role in controlling blood pressure and cardiovascular function as well as in regulating the body's use of proteins, carbohydrates, and fats. As such HSD-1 has been implicated in the development of obesity and type II diabetes. By pursuing inhibitors of HSD-1, Syrrx seeks to augment its growing portfolio of efforts directed at treating type II diabetes, obesity, high cholesterol and other metabolic syndromes.

The structure reported today formed part of the basis for the drug discovery collaboration between Roche and Syrrx, Inc. that was announced in May 2004. As part of that collaboration agreement, Roche made an equity investment in Syrrx convertible preferred stock, and agreed to provide additional funding for research, preclinical, and clinical studies of HSD-1 inhibitors, potentially through to completion of Phase II development. In the event of approval to market a drug product, Syrrx would receive a royalty on drug sales, as well as milestone payments upon the occurrence of certain clinical and regulatory events.

Syrrx determined the structure of HSD-1 in 2003, and has since used the information to design a large collection of novel small-molecule HSD-1 inhibitors. Stephen W. Kaldor, Syrrx president and chief scientific officer, explained, "I am pleased with the rapid progression of our program. In addition to the structural data, we have generated potent and proprietary HSD-1 inhibitors with promising properties in a very short time frame. With continued scientific success, we may be able to begin human testing of Syrrx-designed HSD-1 inhibitors in an aggressive timeframe."

The HSD-1 structure was determined using Syrrx's state-of-the-art Nanovolume Crystallization(R) technology to crystallize disease-associated proteins. Syrrx's HSD-1 structure will appear in an upcoming issue of The Journal of Biological Chemistry. The paper can be read online at http://www.jbc.org/cgi/content/abstract/M411104200v1

"Our proprietary sub-microliter approach to crystallography enabled the rapid generation of the HSD-1 structure, which provided novel insights into the enzyme's mechanism, and established a framework for our inhibitor design program," said David Hosfield, first author of the Syrrx HSD-1 paper. Kathleen Aertgeerts, co-author, added, "We have already determined more than 50 co-complexes in this program, and these data are providing a key advantage in our drug discovery efforts." The remaining authors of the Syrrx paper include Yiqin Wu, Robert Skene, Mark Hilgers, Andy Jennings, and Gyorgy Snell.

According to the American Diabetes Association, almost 17 million Americans have diabetes. This accounts for approximately six percent of the entire U.S. population, including 20 percent of people over the age of 65. Type II diabetes accounts for approximately 90 percent of the diabetes population, with approximately one million new cases of type II diabetes patients diagnosed each year.

Diabetes is a lifelong, chronic and often debilitating disease that develops when the body cannot effectively control the level of sugar (glucose) in the blood stream due to the body's reduced ability to respond to insulin. Studies have demonstrated that HSD-1 is likely a key player in the development of central obesity, a major contributor to the development of type II diabetes, as well as insulin resistance. Inhibitors of HSD-1, which have been shown to block the conversion of cortisone to cortisol in liver and fat tissue, may be of great value in the treatment of the increasing population of patients in the developing world with metabolic syndromes.

About Syrrx

Headquartered in San Diego, California, privately held Syrrx focuses on drug targets that have been validated in human clinical trials and directs its efforts toward therapeutics to treat cancer, metabolic diseases and inflammation. Syrrx exploits its competitive advantage in high-throughput structural biology to be the first organization to determine the three dimensional structure of known drug targets. Syrrx then uses these structures to drive iterative, structure-based drug design programs to efficiently generate potential drug candidates. Syrrx Inc. has an ongoing partnership with PPD (Nasdaq:PPDI) for the joint development and commercialization of Syrrx-designed human dipeptidyl peptidase IV (DPP IV) inhibitors as drug products for the treatment of type 2 diabetes and other major human diseases. Syrrx also recently established a strategic alliance with Roche for the discovery and early development of inhibitors targeting human HDACs and HSD-1. For more information, please consult www.syrrx.com

Source: Business Wire

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