Thursday February 5, 6:29 am Eastern Time
Company Press Release
Nature Publication Reveals AXYS Pharmaceuticals' Delta Technology
SOUTH SAN FRANCISCO--(BW HealthWire)--Feb. 5, 1998--The role of zinc in enhancing both the potency and selectivity of certain small molecule protease inhibitors was revealed today by scientists at AXYS Pharmaceuticals Inc. (NASDAQ:AXPH - news) in collaboration with the Department of Biochemistry of the University of California, San Francisco, writing in the Feb. 5, 1998 issue of Nature.
The article, entitled ''Design of Potent, Selective Zinc-Mediated Serine Protease Inhibitors,'' describes a unique structural paradigm, previously referred to only as ''the Delta Technology,'' which was discovered using a combination of structure-based drug design, crystallographic methods and enzymology.
The design technology was until now formally kept as a trade secret by AXYS Pharmaceuticals and the five pharmaceutical partners that are collaborating with AXYS to apply the technology to develop therapeutics for a variety of diseases.
The authors of the publication are Bradley A. Katz, James M. Clark, Janet S. Finer-Moore, Thomas E. Jenkins, Charles R. Johnson, Michael J. Ross, Christine Luong, William R. Moore, and Robert M. Stroud.
The publication describes the Delta mode of serine protease inhibition as a structure-based drug design motif that is contingent upon creating a zinc binding site at the active site of the enzyme. With the zinc binding site in place, Delta enables the anchoring of a protease inhibitor to a primary site, as well as a secondary anchoring with a side chain in a pocket of the enzyme, producing both potency and specificity simultaneously.
By designing inhibitors that take advantage of this enhanced binding mode, the authors indicate that the Delta Technology can be re-engineered for each enzyme target to take advantage of physiologically relevant quantities of zinc (the Delta component) that are available in the body. To illustrate the potential of the technology, a number of prototype inhibitors of various serine proteases are described in the paper.
According to Dr. Michael Venuti, senior vice president, research, AXYS/South San Francisco: ''Many proteases are targets for therapeutic intervention because they play key roles in disease. By probing the structural basis of inhibition, we discovered, using crystallographic methods, a new mode of high affinity binding in which a Zn+2 ion is tetrahedrally coordinated between two chelating nitrogens of an inhibitor and two active site residues, His-57 and Ser-195. Zinc, at sub-physiological levels, enhances inhibition, sometimes by a thousand-fold and up to 17,000-fold.''
Professor Robert Stroud of the University of California, San Francisco, a primary author of the paper indicated: ''Where most drug design efforts focus on generating high affinity for the target protein, 'positive selection,' they rely on other similar proteins being somewhat less than optimal for selectivity.
''The Delta principle easily achieves high affinity, and interacts with the underexplored unique regions of the proteins for 'negative' selectivity against inhibiting the non-target proteins. The manuscript demonstrates enhancement in the selectivity typically in the range 20 to 5,000-fold.''
Venuti continued, ''This unique structural paradigm has enabled AXYS to develop potent, highly selective, Zn+2-dependent inhibitors of several therapeutically important serine proteases which make use of this physiologically ubiquitous metal ion. As such, the Delta Technology has yielded useful scaffolds from which to potentially develop highly selective drugs.
''Perhaps most importantly, the drug candidates created with the Delta motif have the characteristics of oral drugs, specifically, a low molecular weight and simple non-peptidic structures. This is an important finding, since many traditional drug design approaches have failed to yield highly specific and potent protease inhibitors and were not amenable to oral delivery.''
The ''Delta Technology'' was issued a patent by the United States Patent and Trademark Office, Patent No. 5,693,515, entitled ''Metal Complexed Serine Protease Inhibitors,'' on Dec. 2, 1997.
TECHNICAL BRIEFING TOMORROW MORNING IN NEW YORK CITY
AXYS Pharmaceuticals Inc. announced that at 7:45 a.m. (EST) tomorrow, it is hosting a technical briefing session for Wall Street analysts and investors at the St. Regis Hotel, Iridium Suite, in New York City. Dr. Michael Venuti, AXYS Pharmaceuticals' senior vice president, drug discovery, will describe the Delta Technology and respond to questions. Advance registration is recommended at 650/829-1139.
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