TAILIEUCHUNG - Báo cáo khoa học: Lending a helping hand, screening chemical libraries for compounds that enhance b-hexosaminidase A activity in GM2 gangliosidosis cells

Enzyme enhancement therapy is an emerging therapeutic approach that has the potential to treat many genetic diseases. Candidate diseases are those associated with a mutant protein that has difficulty folding and⁄or assembling into active oligomers in the endoplasmic reticulum. | ỊFEBS Journal MINIREVIEW Lending a helping hand screening chemical libraries for compounds that enhance b-hexosaminidase A activity in GM2 gangliosidosis cells Michael B. Tropak1 and Don Mahuran1 2 1 Research Institute SickKids Toronto Ontario Canada 2 Department of Laboratory Medicine and Pathology University of Toronto Ontario Canada Keywords active-site-specific chaperones enzyme enhancement therapy hexosaminidase high throughput screening lysosomal pharmacological chaperones post translational regulation Sandhoff subunit assembly Tay-Sachs Correspondence D. Mahuran Research Institute Room 9146A Elm Wing Hospitalfor Sick Children 555 University Avenue Toronto Ontario M5G 1X8 Canada Fax 1 416 8138700 Tel 1 416 8136161 E-mail hex@ Received 8 June 2007 accepted 1 August 2007 doi Enzyme enhancement therapy is an emerging therapeutic approach that has the potential to treat many genetic diseases. Candidate diseases are those associated with a mutant protein that has difficulty folding and or assembling into active oligomers in the endoplasmic reticulum. Many lysosomal storage diseases are candidates for enzyme enhancement therapy and have the additional advantage of requiring only 5-10 of normal enzyme levels to reduce and or prevent substrate accumulation. Our long experience in working with the b-hexosaminidase EC isozymes system and its associated deficiencies Tay-Sachs and Sandhoff disease lead us to search for possible enzyme enhancement therapy-agents that could treat the chronic forms of these diseases which express 2-5 residual activity. Pharmacological chaperones are enzyme enhancement therapy-agents that are competitive inhibitors of the target enzyme. Each of the known b-hex-osaminidase inhibitors low IM IC50 increased mutant enzyme levels to 10 in chronic Tay-Sachs fibroblasts and also attenuated the thermodenaturation of b-hexosaminidase. To expand the repertoire of pharmacological chaperones to more .

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