High Throughput Screening for Inhibitors of Alpha-Galactosidase

Omid Motabar1, 2, Ke Liu1, Noel Southall1, Juan J Marugan1, Ehud Goldin2, Ellen Sidransky2, Wei Zheng*, 1
1 NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-3370, USA
2 Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-3370, USA

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© Motabar et al.; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

* Address correspondence to this author at the 9800 Medical Center Drive, MSC 3370, Bethesda, MD 20892-3370, Tel: 301-217-5720; Fax: 301-217-5728; E-mail:


Fabry disease is a rare X-linked lysosomal storage disorder caused by a deficiency in α-galactosidase A (GLA), which catalyzes the hydrolysis of terminal α-galactosyl groups from glycosphingolipids, such as globotriaosylceramide (Gb3). Many of the mutations in the GLA gene are missense alterations that cause misfolding, decreased stability, and/or mistrafficking of this protein. Small molecule compounds that correct the misfolding and mistrafficking, or activate the mutant enzyme, may be useful in the treatment of Fabry disease. We have screened a library of approximately 230,000 compounds using preparations of human recombinant protein and purified coffee bean enzyme in an effort to find activators and inhibitors of this enzyme. Lansoprazole was identified as a small molecule inhibitor of GLA derived from coffee beans (IC50 = 6.4 μM), but no inhibitors or activators were identified for the human enzyme. The screening results indicate that human GLA is a difficult target for small molecule inhibition or activation.

Keywords: Alpha-galactosidase, inhibitor, Fabry disease, drug target, high throughput screening.