INRS-Institut Armand-Frappier, Groupe de Recherche en Ingénierie des Peptides et en Pharmacothérapie (GRIPP) , Université du Québec , Ville de Laval , Québec H7V 1B7 , Canada.
Department of Pharmacology and Therapeutics , McGill University , Montréal , Québec H3A 1A3 , Canada.
J Med Chem. 2018 Oct 11;61(19):8707-8716. doi: 10.1021/acs.jmedchem.8b00789. Epub 2018 Sep 19.
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 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, G, and β-arrestin 1 signaling pathways. Such modifications impaired contractile efficacy, reflected by a reduced aptitude to activate G in URP but not in the truncated but equipotent UII. Moreover, we have identified two structurally different UT modulators: [d-Phe(pI)]URP and [Bip]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.
尾加压素 II（UII）和尾加压素 II 相关肽（URP）具有功能选择性，表明这两种激素可能通过与其同源受体 UT 的不同相互作用发挥不同的生理作用。假设 URP 中的苯丙氨酸残基（也存在于 UII 中）是其特异性 UT 激活的关键要素，我们评估了用非天然氨基酸替代 URP 中苯丙氨酸残基的影响。评估了每种化合物与 UT 结合、诱导大鼠主动脉环收缩以及激活 G、G 和β-arrestin 1 信号通路的能力。这些修饰损害了收缩效力，反映出 URP 中激活 G 的能力降低，但在截短但等效的 UII 中则没有。此外，我们已经鉴定出两种结构不同的 UT 调节剂：[d-Phe(pI)]URP 和 [Bip]URP，它们对 UII 和 URP 具有探针依赖性作用。这些化合物应该有助于我们理解这些激素的特定作用，并指导进一步的治疗开发。
