Injectable, degradation-resistant analogues of glucagon-like peptide-1 (GLP1), which function as full agonists of the GLP1 receptor (GLP1R), have proven efficacious in diabetes treatment. Conversely, because of the size and complexity of the orthosteric (agonist) binding site, small molecule drug discovery/development has lagged in providing orally bio-available medications. Therefore, allosteric modulation provides an attractive strategy to therapeutically target GLP1R signaling. We hypothesize that allosteric modulators can both enhance the efficacy of native and pharmacological othosteric agonists and also be engineered to take advantage of signaling bias and thereby direct signaling events toward unique cellular outcomes. While GLP1 clearly potentiates -cell insulin secretion, receptors are distributed throughout the body and also have salutary effects on a range of biology, including -cell proliferation, appetite, cognition, and others. Thus, the ability to fine tune GLP1R intracellular signaling events offers the opportunity to enhance our understanding of GLP1 biology, and ultimately, to improve human health. We have developed positive allosteric modulators (PAMs) of the GLP1R using high-throughput screening, secondary, tertiary, and quaternary screening, medicinal chemistry, and preliminary drug metabolism and pharmacokinetics (DMPK). The goals of the current proposal are to, in parallel, develop my professional skills AND advance the project. The objectives of this study are (1) to complete a thorough molecular pharmacological analysis, including signaling bias, of our portfolio of GLP1R small molecule positive allosteric modulators, (2) to develop my skills and apply initial in vitro and in vivo drug metabolism and pharmacokinetics (DMPK) strategies to novel GLP1R PAMs in order to develop a lead(s) for in vivo physiological efficacy testing, and (3) to rigorously test te translational hypothesis that GLP1R PAM(s) will significantly enhance the effects of native GLP1 and therapeutic analogues in vivo in preclinical rodent models.
Because obesity and diabetes are at epidemic proportions, this study aims to address a critical public health concern by investigating and characterizing therapies that may have beneficial effects on weight loss and insulin release from the pancreas. The development of positive allosteric modulators (PAMs) of the glucagon- like peptide-1 receptor (GLP-1R) would provide an orally-available supplement to enhance current diabetes therapies, prevent undesirable side effects, and increase the probability of long-term adherence to the therapy. The potential of these compounds to enhance insulin secretion from the pancreas will be investigated, and this therapeutic strategy may ultimately prove disease-modifying in this progressive and common metabolic disorder.
