Expanding Structure–Activity Relationships of Human Urotensin II Peptide Analogues: A Proposed Key Role of the N‑Terminal Region for Novel Urotensin II Receptor Modulators

While
the urotensinergic system plays a role in influencing various
pathologies, its potential remains untapped because of the absence
of therapeutically effective urotensin II receptor (UTR) modulators.
Herein, we developed analogues of human urotensin II (hU-II) peptide in which, along with well-known antagonist-oriented
modifications, the Glu1 residue was subjected to single-point
mutations. The generated library was tested by a calcium mobilization
assay and ex vivo experiments, also in competition with selected ligands.
Interestingly, many derivatives showed noncompetitive modulation that
was rationalized by the lateral allostery concept applied to a G protein-coupled
receptor (GPCR) multimeric model. UPG-108 showed an unprecedented
ability to double the efficacy of hU-II, while UPG-109 and UPG-111 turned out
to be negative allosteric modulators of UTR. Overall, our investigation
will serve to explore and highlight the expanding possibilities of
modulating the UTR system through N-terminally modified hU-II analogues and, furthermore, will aim to elucidate
the intricate nature of such a GPCR system.

尽管尿紧张素能系统（urotensinergic system）在多种病理进程中发挥调控作用，但由于缺乏治疗有效的尿紧张素II受体（UTR）调节剂，其潜在应用价值仍未被充分挖掘。本研究针对人类尿紧张素II（hU-II）肽开发了一系列类似物：在保留经典拮抗剂导向修饰的基础上，对第1位谷氨酸（Glu1）残基进行了单点突变。通过钙动员检测与离体实验对所构建的化合物库进行活性评价，同时联合选定配体开展竞争结合实验。有趣的是，多数衍生物展现出非竞争性调控活性，这一现象可通过应用于G蛋白偶联受体（GPCR）多聚体模型的侧向变构（lateral allostery）概念得到合理解释。其中UPG-108展现出前所未有的活性，可将hU-II的效能提升一倍；而UPG-109与UPG-111则被证实为UTR的负变构调节剂。综上，本研究通过构建N端修饰的hU-II类似物库，为探索靶向UTR系统的调控策略提供了新的可能性，同时也旨在阐明此类GPCR系统复杂的调控本质。