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• W2914881750 abstract "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." @default.
• W2914881750 created "2019-02-21" @default.
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• W2914881750 date "2019-04-01" @default.
• W2914881750 modified "2023-10-10" @default.
• W2914881750 title "Rationally designed small molecules to prevent type 1 diabetes" @default.
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• W2914881750 doi "https://doi.org/10.1097/med.0000000000000470" @default.
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