Electronic Resource
Structure-Activity Studies of A-Melanotropin and Ultra-Short Glp-1 Analogs To Benchmark the Development of Improved Anti-Obesity Drugs
| العنوان: | Structure-Activity Studies of A-Melanotropin and Ultra-Short Glp-1 Analogs To Benchmark the Development of Improved Anti-Obesity Drugs |
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| المؤلفون: | Jewett, John C., Cai, Minying, Charest, Pascale G., Mash, Eugene A., Sawyer, Jonathon Randall |
| بيانات النشر: | The University of Arizona. 2022 |
| نوع الوثيقة: | Electronic Resource |
| مستخلص: | Metabolic disease has become a major health epidemic throughout the world. There are several receptor systems that have been previously determined to alter energy balance and induce obesity. Two of these receptor systems, namely the melanocortin receptor (MCR) system and glucagon-like peptide 1 (GLP-1), were investigated further due to their critical roles in the complex neural network involved in energy homeostasis. Research into both systems uncovered two key peptides in the literature, one for each receptor system, that have significant potential for development. The first peptide is an FDA approved MCR drug, known as Setmelanotide, which is used to treat MC4R- and leptin-deficiency induced obesity (both orphan diseases). The second peptide is an ultra-short GLP-1 analog called BMS-686117 that is highly potent and efficacious.Herein, traditional medicinal chemistry studies were performed on both Setmelanotide and an ultra-short GLP-1 analog (simplified BMS-686117) to understand their structure-activity relationship (SAR) at their respective receptor target. The SAR studies performed on these two ligands at MCR and/or GLP-1 encompass various alanine scans (MCR and GLP-1), a chirality inversion walk (MCR), backbone constraints (MCR), an aminoisobutyric acid (Aib) scan (GLP- 1), and a Phe6 scan (GLP-1). Such efforts uncovered several key findings for both peptides. On Setmelanotide it was determined that: (1) Position 5 can be exploited for MCR agonist/antagonist selectivity, (2) His4, Arg6, and Trp7 are important for potency, and (3) Arg1 and D-Ala3 are not critical for potency and efficacy. For the ultra-short GLP-1 analog it was discovered that (1) incorporation of a-helical inducing residues increases potency, and (2) His1, Aib2, Glu3, Thr5, Ser8, and Bip11 are positions that can be investigated further in future SAR studies. These results provide substantial information that will lead to future analog designs of these two peptides with the potential of the deve |
| مصطلحات الفهرس: | text, Electronic Dissertation |
| URL: | |
| الاتاحة: | Open access content. Open access content http://rightsstatements.org/vocab/InC/1.0 Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction, presentation (such as public display or performance) of protected items is prohibited except with permission of the author. |
| Other Numbers: | AZU oai:repository.arizona.edu:10150/667619 Sawyer, Jonathon Randall. (2022). Structure-Activity Studies of A-Melanotropin and Ultra-Short Glp-1 Analogs To Benchmark the Development of Improved Anti-Obesity Drugs (Doctoral dissertation, University of Arizona, Tucson, USA). 1373211750 |
| المصدر المساهم: | UNIV OF ARIZONA From OAIster®, provided by the OCLC Cooperative. |
| رقم الانضمام: | edsoai.on1373211750 |
| قاعدة البيانات: | OAIster |
| الوصف غير متاح. |