A Non-Perturbative Molecular Grafting Strategy for Stable and Potent Therapeutic Peptide Ligands
| Autor: | Alan S. Kopin, Martin Beinborn, Micaella P Fagan, Jamie R. Doyle, David R. Haines, Maribel Rios, Kathleen M Sicinski, Venkata S. Raman, Yi Chi Song, Krishna Kumar, Vittorio Montanari, Benjamin N. Harwood |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
chemistry.chemical_classification
Agonist Serine protease biology 010405 organic chemistry medicine.drug_class General Chemical Engineering Incretin Peptide General Chemistry Secretin family 010402 general chemistry 01 natural sciences Glucagon 0104 chemical sciences Cell biology Chemistry chemistry medicine biology.protein Receptor QD1-999 Function (biology) Research Article |
| Zdroj: | ACS Central Science, Vol 7, Iss 3, Pp 454-466 (2021) ACS Central Science |
| ISSN: | 2374-7951 |
| Popis: | The gut-derived incretin hormone, glucagon-like peptide-1 (GLP1), plays an important physiological role in attenuating post-prandial blood glucose excursions in part by amplifying pancreatic insulin secretion. Native GLP1 is rapidly degraded by the serine protease, dipeptidyl peptidase-4 (DPP4); however, enzyme-resistant analogues of this 30-amino-acid peptide provide an effective therapy for type 2 diabetes (T2D) and can curb obesity via complementary functions in the brain. In addition to its medical relevance, the incretin system provides a fertile arena for exploring how to better separate agonist function at cognate receptors versus susceptibility of peptides to DPP4-induced degradation. We have discovered that novel chemical decorations can make GLP1 and its analogues completely DPP4 resistant while fully preserving GLP1 receptor activity. This strategy is also applicable to other therapeutic ligands, namely, glucose-dependent insulinotropic polypeptide (GIP), glucagon, and glucagon-like peptide-2 (GLP2), targeting the secretin family of receptors. The versatility of the approach offers hundreds of active compounds based on any template that target these receptors. These observations should allow for rapid optimization of pharmacological properties and because the appendages are in a position crucial to receptor stimulation, they proffer the possibility of conferring “biased” signaling and in turn minimizing side effects. Diverse N-terminal modifications of various peptide templates render them refractory to protease action and retain full biological activity. These constructs have potential for development of therapeutics for many diseases. |
| Databáze: | OpenAIRE |
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