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Selectin Binding Inhibitors and Selectin Ligand Metabolic Inhibitors

Dr. Professor Khushi L Matta, Chief Scientist, a carbohydrate synthesis expert in metabolic biosynthesis of cell surface carbohydrates has developed a series of compounds targeting inflammation and cancer.  Provisional Patents have been filed on these compounds and their indications.

TumorEnd can hold meetings with interested entities under Confidentiality Agreements to discuss the details of structures and targets.  We have a small molecular weight compound that specifically inhibits biosynthesis of the E-selectin Ligand, key in inflammation.  We have inexpensive neutral small molecules that inhibit binding of P and L selectins.  These are being developed for anti-inflammatory targets. 

The research efforts in his laboratory have been primarily made with glycobiology projects at the interface of chemistry and biology. For example, small synthetic carbohydrate molecules and their modified analogs used as acceptors for glycosyltransferases allowed identification of novel β-GlcNAc-transferases involved in the assembly of unique O-glycans. Similarly, based upon reports in early year 1990, that glycans containing sialyl LeX and sialyl LeA act as ligands for selectins (E and P), and that GlyCAM-1 (a mucin glycoprotein) binds with L selectin. Matta hypothesized that detailed knowledge of the levels of sialyl-, fucosyl-, and sulfo-T biosynthetic activities could provide key insights into the possible structure of the native selectin-ligands. This hypothesis led to the prediction that a core-2 branched tetra-saccharide Gal4(sulfo 6GlcNAc)-6(Gal 3)-GalNAc was part of the selectin-ligand and culminated in the synthesis of 3-O-sulfated Lewisx. This work was confirmed subsequently by multiple investigators. In Matta's laboratory, the prime theme is to synthesize only those specific carbohydrates that can be used for some specific biomedical properties. The investigative power of his synthetic acceptor library became evident as he discovered two distinct Gal:3-O-sulfoTs activities in cancer tissues one being specific for T-hapten Gal3GalNAc- (in breast cancer tissues &some some cell lines to generate SE-3Gal3GalNAc- and another shows preference for Gal4GlcNAc terminal unit in Core 2 tetrasaccharide Gal4GlcNAcβ6(Gal3)GalNAcα. The latter enzyme is expressed in colon cancer and some breast cell lines.  These may be biomarkers for diagnostics or targets for inhibitors.

Dr Matta's solid background in chemistry of carbohydrate has been instrumental in identifying specificities of various enzymes and biosynthesis of glycans. This has allowed me to set up collaborations with various research groups. Chemistry can provide an array of well defined structures to define the specificity of enzymes and other carbohydrate binding proteins. His approach of profiling of enzymes has identified culprit enzymes responsible for further biochemical studies . Among the family of sialyltransferases, ST3GalTs became a subject of studies. Unexpectedly, he discovered an intriguing “reversible property” and exchange property of this enzyme . The exchange property is very effective for radio labeling of Neu5Acα in the Neu5Acα2,3Galβ3GalNAc sequence of O-glycans and glycolipids and is different from direct sialylation of glycans containing naked Galβ3GalNAc using a sialylT and a labeled CMP-Sia donor. Thus, the two intriguing and unexpected properties provide innovative technologies, a start of new paradigm in specific evaluation of Siaα2,3Galβ3GalNAc signatures that includes Neu5Gcα2,3Galβ3GalNAc and may have diagnostic and therapeutic value.

Matta's laboratory synthesized 4 fluoro-GlcNAc acetate which decoy for the biosynthesis of glycans and has a patent with a Boston group. He also synthesized 4 fluoro-GalNAc acetate and tested it as a metabolic inhibitor of both O-glycans and chondroitin sulfate. Dr. Jeffrey Esko, San Diego, collaborated with us on the use of small disaccharide acetate as decoys for biosynthesis of cell adhesion proteins. In a nut shell, Matta's solid background in making use of carbohydrate acceptors for enzymes, synthesis of glycan target compound and use of small molecules as decoys/metabolic inhibitors is leading to new, promising candidate anti-inflammatories.

The prime theme is to synthesize only those specific carbohydrates that can be used for some specific biochemical properties. We identify specificities of various enzymes and biosynthesis of glycans. 

After 40 years at the Roswell Park Memorial Cancer Research Center, Buffalo, NY, Matta moved his laboratory to TumorEnd, LCC.