ESPE Abstracts (2015) 84 WG4.2

A Monomeric Peptide Triagonist for the Treatment of Obesity and Diabetes

Christoffer Clemmensena, Brian Finana, Timo Müllera, Richard DiMarchib & Matthias Tschöpa

aInstitute for Diabetes and Obesity, Helmholtz Zentrum Munich, Munich, Germany; bDepartment of Chemistry, Indiana University, Bloomington, Illinois, USA

Encouraged by unimolecular dual incretin co-agonists (GLP1/GIP) to enhance glycemic efficacy (Finan et al. 2013, Sci Transl Med) and GLP1/glucagon co-agonists to enhance weight loss efficacy (Day et al. 2009, Nat Chem Biol) and to restore diet-induced leptin sensitivity (Clemmensen et al. 2014, Diabetes), we recently developed the first tri-agonist (GLP1/GIP/glucagon) for the treatment of metabolic disorders (Finan et al. 2014, Nat Med). Importantly, this concerted triple agonism outperforms the aforementioned co-agonists by synergistically harnessing the attributes of each constituent hormone, ultimately resulting in benefits that rival those of bariatric surgeries. Another strategy we are currently pursuing involves incretin-based delivery of nuclear hormones in order to gain synergistic effects while restricting hallmark toxicities of the nuclear hormone, all of which is governed by the use of incretins as a chaperone to selectively target the nuclear hormones to certain tissues (Finan et al. 2012, Nat Med). In summary, incretin pharmacology can be enhanced or exploited through integration of complementary peptide agonism or through targeting of nuclear hormones. This pharmacological strategy may provide unprecedented opportunities in the personalized treatment of heterogeneous metabolic diseases.

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