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Discovery, structure-activity relationship, and biological evaluation of noninhibitory small molecule chaperones of glucocerebrosidase.

ABSTRACT: A major challenge in the field of Gaucher disease has been the development of new therapeutic strategies including molecular chaperones. All previously described chaperones of glucocerebrosidase are enzyme inhibitors, which complicates their clinical development because their chaperone activity must be balanced against the functional inhibition of the enzyme. Using a novel high throughput screening methodology, we identified a chemical series that does not inhibit the enzyme but can still facilitate its translocation to the lysosome as measured by immunostaining of glucocerebrosidase in patient fibroblasts. These compounds provide the basis for the development of a novel approach toward small molecule treatment for patients with Gaucher disease.

SUBMITTER: Patnaik S

PROVIDER: S-EPMC3400126 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Discovery, structure-activity relationship, and biological evaluation of noninhibitory small molecule chaperones of glucocerebrosidase.

Patnaik Samarjit S Zheng Wei W Choi Jae H JH Motabar Omid O Southall Noel N Westbroek Wendy W Lea Wendy A WA Velayati Arash A Goldin Ehud E Sidransky Ellen E Leister William W Marugan Juan J JJ

Journal of medicinal chemistry 20120608 12

A major challenge in the field of Gaucher disease has been the development of new therapeutic strategies including molecular chaperones. All previously described chaperones of glucocerebrosidase are enzyme inhibitors, which complicates their clinical development because their chaperone activity must be balanced against the functional inhibition of the enzyme. Using a novel high throughput screening methodology, we identified a chemical series that does not inhibit the enzyme but can still facili ...[more]

PMID: 22646221

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