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Rationally designed small molecules to prevent type 1 diabetes

Ostrov, David A.a; Gottlieb, Peter A.b; Michels, Aaron W.b

Current Opinion in Endocrinology, Diabetes and Obesity: April 2019 - Volume 26 - Issue 2 - p 90–95
doi: 10.1097/MED.0000000000000470

Purpose of review To review the recent findings that small ‘drug-like’ compounds block disease-specific human leukocyte antigen (HLA) molecules in type 1 diabetes (T1D).

Recent findings The predominant genetic risk for developing T1D, the immune-mediated form of diabetes, is conferred through HLA genes. One such gene, termed HLA-DQ8, is present in 50–60% of patients with T1D and those at-risk. DQ8 presents disease-relevant peptides to T cells, which mediate tissue-specific destruction of pancreatic islets. Using a structure-based approach to evaluate the ‘druggability’ of the DQ8 molecule, methyldopa, a clinically well-established oral antihypertensive agent, was discovered to bind DQ8. Methyldopa blocked the activation of DQ8-specific T cells responding to self-antigens such as insulin but not influenza. In a proof-of-concept clinical trial (NCT01883804), methyldopa was administered to recent-onset T1D patients with the DQ8 gene that confirmed the mechanism of action and diminished inflammatory T cell responses toward insulin.

Summary Methyldopa blocks the diabetes-specific function of HLA-DQ8, which represents a personalized medicine approach to treat the underlying autoimmunity in T1D. Clinical trials are warranted and underway to evaluate methyldopa in potentially preserving residual β-cell function in those with new onset and at risk for T1D.

aDepartment of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida

bDepartments of Pediatrics and Medicine, Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, Colorado, USA

Correspondence to Aaron W. Michels, MD, Barbara Davis Center for Diabetes, University of Colorado Denver, 1775 Aurora Court, MS A140, Aurora, CO 80045, USA. Tel: +1 303 724 1923; fax: +1 303 724 6784; e-mail:

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