Rationally designed small molecules to prevent type 1 diabetes

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.

Conflict of interest statement

Conflicts of Interest

A.W. Michels and D.A. Ostrov are inventors on a patent, Compounds That Modulate Autoimmunity and Methods of Using the Same, licensed to ImmunoMolecular Therapeutics. A.W. Michels and P.A. Gottlieb are scientific cofounders of ImmunoMolecular Therapeutics and own shares in the company.

Figures

Figure 1.

Structure-based approach to identify small ‘drug-like’ compounds binding to the type 1 diabetes risk HLA-DQ8 molecule. Using the crystal structure of DQ8, molecular modeling and docking was performed with a library of small molecules into each of the four pockets (P1, P4, P6, and P9) in the peptide-binding groove. Free energy of binding was estimated and the top 40 scoring compounds were further tested with an in vitro T cell bioassay. Lead compounds were selected based upon off target, specificity, and in vivo testing. Methyldopa (Aldomet), which is an oral FDA approved drug to treat hypertension in both children and adults, was identified through this approach. Methyldopa was repurposed and used to treat recent-onset T1D patients with DQ8 in a proof-of-mechanism clinical trial.

Figure 2.

Molecular models of methyldopa in the DQ8 peptide-binding groove. (A) Methyldopa is shown within pocket 6 of DQ8. There are hydrogen bonds between methyldopa and asparagine (ASN) at position 62 of the DQ8 alpha chain and tyrosine (Tyr) at position 30 of the DQ8 beta chain. These hydrogen bonds were confirmed in structure activity relationship testing using modified methyldopa compounds. (B) Methyldopa in the DQ8 peptide-binding groove clashing with the binding of an insulin peptide. Images were generated using PYMOL software.