Discovery of New Allosteric Modulators of the Urotensinergic System through Substitution of the Urotensin II-Related Peptide (URP) Phenylalanine Residue
Discovery of New Allosteric Modulators of the Urotensinergic System through Substitution of the Urotensin II-Related Peptide (URP) Phenylalanine Residue
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DOI：
10.1021/acs.jmedchem.8b00789
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发表时间：
2018-10-11
影响因子：
7.3
通讯作者：
Chatenet, David
中科院分区：
文献类型：
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作者：
Billard, Etienne;Hebert, Terence E.;Chatenet, David
Urotensin II (UII) and urotensin II-related peptide (URP) are functionally selective, suggesting that these two hormones might play distinct physiological role through different interactions with their cognate receptor UT. Hypothesizing that the Phe(3) residue of URP, which is also present in UII, is a key-element of its specific UT activation, we evaluated the impact of its replacement by non-natural amino acids in URP. Each compound was evaluated for its ability to bind UT, induce rat aortic ring contraction, and activate G(q), G(12), and beta-arrestin 1 signaling pathways. Such modifications impaired contractile efficacy, reflected by a reduced aptitude to activate G(12) in URP but not in the truncated but equipotent UII4-11. Moreover, we have identified two structurally different UT modulators: [D-Phe(pI)(3)]URP and [Bip(3)]URP, which exert a probe-dependent action against UII and URP. These compounds should help us understand the specific roles of these hormones as well as guide further therapeutic development.
