作为甲酰肽受体-1 拮抗剂的转折肽类似物

IF 4.9 Q1 CHEMISTRY, MEDICINAL ACS Pharmacology and Translational Science Pub Date : 2024-10-23 eCollection Date: 2024-11-08 DOI:10.1021/acsptsci.4c00366

Maria De Fenza, Filippo Locri, Flavia Plastino, Marco Chino, Ornella Maglio, Linda Leone, Giorgia Gazzaroli, Mirella Belleri, Arianna Giacomini, Anders Kvanta, Helder André, Vincenzo Pavone, Daniele D'Alonzo

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引用次数: 0

摘要

本文报告了一种可作为甲酰肽受体（FPR1）拮抗剂的新型拟肽化合物（N-19004）的设计、合成和表征。通过对人类受体上的强效 FPR1 拮抗剂 UPARANT 进行对接研究，确定了该分子。N-19004 以最小的结构重现了识别所需的所有药效基团，其中 2,6-二氨基噻吩支架模仿了 UPARANT 的 Arg-Aib-Arg 转折段中 Arg 残基 Cα 原子的位置，起着至关重要的作用。N-19004 在体外和体内都能干扰 FPR1 的生物特性。在小鼠脉络膜新生血管模型中，N-19004 通过全身给药途径显著缩小了激光诱导的脉络膜病变的大小，并重新吸收了水肿区域。

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Turn-Adopting Peptidomimetic as a Formyl Peptide Receptor-1 Antagonist.

The design, synthesis, and characterization of a new peptidomimetic acting as a formyl peptide receptor (FPR1) antagonist (N-19004) are herein reported. The molecule has been identified with docking studies of the highly potent FPR1 antagonist UPARANT on human receptor. N-19004 recapitulates all pharmacophoric groups necessary for recognition into a minimal structure, with a crucial role of the 2,6-diamino-thiophenyl scaffold mimicking the positions of Cα atoms of Arg residues in the turned Arg-Aib-Arg segment of UPARANT. N-19004 demonstrated to interfere with the biological properties of FPR1 both in vitro and in vivo. In a mouse model of choroidal neovascularization, N-19004 markedly reduced the size of laser-induced choroidal lesions, with reabsorption of the edema regions by a systemic administration route.

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来源期刊

ACS Pharmacology and Translational Science Medicine-Pharmacology (medical)

CiteScore

10.00

自引率

3.30%

发文量

133

期刊介绍： ACS Pharmacology & Translational Science publishes high quality, innovative, and impactful research across the broad spectrum of biological sciences, covering basic and molecular sciences through to translational preclinical studies. Clinical studies that address novel mechanisms of action, and methodological papers that provide innovation, and advance translation, will also be considered. We give priority to studies that fully integrate basic pharmacological and/or biochemical findings into physiological processes that have translational potential in a broad range of biomedical disciplines. Therefore, studies that employ a complementary blend of in vitro and in vivo systems are of particular interest to the journal. Nonetheless, all innovative and impactful research that has an articulated translational relevance will be considered. ACS Pharmacology & Translational Science does not publish research on biological extracts that have unknown concentration or unknown chemical composition. Authors are encouraged to use the pre-submission inquiry mechanism to ensure relevance and appropriateness of research.