U.S. Department of Health and Human Services

Small Molecules Hold Promise to Prevent Type 1 Diabetes

New research has identified promising small molecules to prevent development of type 1 diabetes. Because type 1 diabetes results from inappropriate activity of the immune system, scientists are pursuing potential treatments that suppress this harmful activity. However, many agents that suppress the harmful aspects also suppress the protective aspects of the immune system and, therefore, can have toxic side effects and increase a person’s risk for infection. Scientists are investigating therapies to selectively suppress the specific cells involved in autoimmune diseases like type 1 diabetes. Small molecules have proven valuable for affecting the function of genes, cells, and biological pathways, and hold great promise for the prevention of type 1 diabetes. A key challenge, however, is to identify small molecules that can selectively modulate a specific biological process or disease state. Two recent reports utilized different strategies to find promising new molecules for the prevention of type 1 diabetes. 

In previous work, a group of scientists developed a small molecule that selectively affected Th17 cells—immune system cells that produce a protein called IL-17 and have been previously implicated in autoimmune diseases. They demonstrated that the molecule affected Th17 cells by binding to and repressing two proteins, called RORα and RORγ, whose activity is required for the development of Th17 cells. In new research, these scientists synthesized a modified version of their molecule that selectively binds to and suppresses RORγ, but not RORα. This was done because other research suggested that suppressing RORγ alone inhibits development of Th17 cells, and it is preferable to develop small molecules that specifically target the disease process, to reduce the chance of adverse side effects. This new molecule still inhibits IL-17 production, suggesting that the molecule is a potent repressor of RORγ activity and has potential for the treatment of autoimmune disease. 

Another group of scientists, searching for a potential drug to prevent type 1 diabetes, screened a large library of small molecules and identified one that alters a key autoimmune reaction in this disease. With knowledge of the structure of a protein that confers type 1 diabetes risk (a form of the MHC class II protein), the researchers used computer simulation to identify small molecules that are likely to bind this protein, and then tested these molecules further in experiments with cells and mice. They hypothesized that these small molecules, by binding the protein, could alter how the protein presents insulin to immune cells called T cells, which is important in the development of autoimmunity. Indeed, further analyses demonstrated that certain of these small molecules could enhance or inhibit the T cell response to insulin; enhancing certain types of T cell responses could potentially prevent or dampen autoimmunity. One small molecule they identified, called glyphosine, enhanced a T cell response to insulin in mouse cells, increased production of an anti-inflammatory protein (called IL-10), and, when given to mice genetically susceptible to type 1 diabetes, prevented development of the disease. Importantly, giving glyphosine to human cells from people with type 1 diabetes suggested that it may enhance a protective type of T cell response in humans as well. Further research with these promising small molecules will determine whether they have utility in humans to prevent type 1 diabetes. 

Kumar N, Lyda B, Chang MR, et al. Identification of SR2211: a potent synthetic RORγ-selective modulator. ACS Chem Biol 7: 672-677, 2012. 

Michels AW, Ostrov DA, Zhang L, et al. Structure-based selection of small molecules to alter allele-specific MHC class II antigen presentation. J Immunol 187: 5921-5930, 2011.