1755-P: The Development of Antagonists Targeting Olfr109 to Treat Diabetes

The olfactory receptor Olfr109 is activated in diabetic models and then impairs islet β cell functions. Antagonizing Olfr109 is a new potential therapeutic strategy to treat diabetes. Previous studies showed that pepducin o109-i2-2 targeting Olfr109 improved islet function and glucose homeostasis. To further obtain the higher potency antagonists, we rationally designed the peptide antagonists targeting Olfr109. We successfully convert the peptide agonist insB 9:23 to the antagonist Ssc-S(R) by combining mutations and non-natural amino acid substitution at specific positions. Importantly, the combined antagonist of Ssc-S(R) had a more significant effect on the improvement of glucose metabolism in diabetic mice. In response to Ssc-S(R), the decreased insulin secretion and increased endoplasmic reticulum stress were significantly alleviated. Therapeutic administration of Ssc-S(R) could significantly ameliorate intra-islet inflammatory responses and improved glucose homeostasis in both Akita and HFD-fed mice. Notably, no significant differences were observed in ins2 ^WT/Akita Olfr109^-/- mice and HFD-fed Olfr109^-/- mice. Taken together, we have developed the Olfr109-specific antagonist Ssc-S(R), which may provide new clues for the treatment of islet inflammation and diabetes.