AI Article Synopsis
- NMU and NMS have various physiological effects, including reducing appetite, and function through two specific receptors, NMUR1 and NMUR2, using a key heptapeptide sequence.
- Researchers developed hexapeptide agonists that are selective to these receptors but found they were less effective than the natural ligand hNMU.
- Further studies identified a potent hexapeptide (5d) with similar activity to hNMU, and revealed important stability insights regarding its degradation in rat serum, which can guide future drug development.
Article Abstract
Neuromedin U (NMU) and S (NMS) display various physiological activities, including an anorexigenic effect, and share a common C-terminal heptapeptide-amide sequence that is necessary to activate two NMU receptors (NMUR1 and NMUR2). On the basis of this knowledge, we recently developed hexapeptide agonists 2 and 3, which are highly selective to human NMUR1 and NMUR2, respectively. However, the agonists are still less potent than the endogenous ligand, hNMU. Therefore, we performed an additional structure-activity relationship study, which led to the identification of the more potent hexapeptide 5d that exhibits similar NMUR1-agonistic activity as compared to hNMU. Additionally, we studied the stability of synthesized agonists, including 5d, in rat serum, and identified two major biodegradation sites: Phe(2)-Arg(3) and Arg(5)-Asn(6). The latter was more predominantly cleaved than the former. Moreover, substitution with 4-fluorophenylalanine, as in 5d, enhanced the metabolic stability at Phe(2)-Arg(3). These results provide important information to guide the development of practical hNMU agonists.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4360155 | PMC |
| http://dx.doi.org/10.1021/ml500494j | DOI Listing |
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