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Structure–Activity Relationship and Bioactivity of Short Analogues of ELABELA as Agonists of the Apelin Receptor
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-12-22 , DOI: 10.1021/acs.jmedchem.0c01547 Kien Trân 1, 2 , Alexandre Murza 1, 2 , Xavier Sainsily 1, 2 , Eugénie Delile 2, 3 , Pierre Couvineau 4 , Jérôme Côté 1, 2 , David Coquerel 2, 3 , Maude Peloquin 1 , Mannix Auger-Messier 2, 3 , Michel Bouvier 4 , Olivier Lesur 2, 3 , Philippe Sarret 1, 2 , Éric Marsault 1, 2
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-12-22 , DOI: 10.1021/acs.jmedchem.0c01547 Kien Trân 1, 2 , Alexandre Murza 1, 2 , Xavier Sainsily 1, 2 , Eugénie Delile 2, 3 , Pierre Couvineau 4 , Jérôme Côté 1, 2 , David Coquerel 2, 3 , Maude Peloquin 1 , Mannix Auger-Messier 2, 3 , Michel Bouvier 4 , Olivier Lesur 2, 3 , Philippe Sarret 1, 2 , Éric Marsault 1, 2
Affiliation
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ELABELA (ELA) is the second endogenous ligand of the apelin receptor (APJ). Although apelin-13 and ELA both target APJ, there is limited information on structure–activity relationship (SAR) of ELA. In the present work, we identified the shortest bioactive C-terminal fragment ELA23-32, which possesses high affinity for APJ (Ki 4.6 nM) and produces cardiorenal effects in vivo similar to those of ELA. SAR studies on conserved residues (Leu25, His26, Val29, Pro30, Phe31, Pro32) show that ELA and apelin-13 may interact differently with APJ. His26 and Val29 emerge as important for ELA binding. Docking and binding experiments suggest that Phe31 of ELA may bind to a tight groove distinct from that of Phe13 of Ape13, while the Phe13 pocket may be occupied by Pro32 of ELA. Further characterization of signaling profiles on the Gαi1, Gα12, and β-arrestin2 pathways reveals the importance of aromatic residue at the Phe31 or Pro32 position for receptor activation.
中文翻译：
ELABELA短类似物作为Apelin受体激动剂的结构-活性关系和生物活性
ELABELA（ELA）是apelin受体（APJ）的第二个内源性配体。尽管apelin-13和ELA均以APJ为靶标，但关于ELA的构效关系（SAR）的信息有限。在目前的工作中，我们确定了最短的生物活性C端片段ELA23-32，它对APJ具有高亲和力（K i 4.6 nM）并在体内产生心肾作用与ELA类似。对保守残基（Leu25，His26，Val29，Pro30，Phe31，Pro32）的SAR研究表明，ELA和apelin-13与APJ的相互作用可能不同。His26和Val29对于ELA结合显得很重要。对接和结合实验表明，ELA的Phe31可能与不同于Ape13的Phe13的紧密凹槽结合，而Phe13的口袋可能被ELA的Pro32占据。对Gα信令型材的进一步表征I1，Gα 12，和β-arrestin2的途径揭示了芳族残基的受体活化的Phe31或Pro32位置的重要性。
更新日期：2021-01-14
中文翻译：
ELABELA短类似物作为Apelin受体激动剂的结构-活性关系和生物活性
ELABELA（ELA）是apelin受体（APJ）的第二个内源性配体。尽管apelin-13和ELA均以APJ为靶标，但关于ELA的构效关系（SAR）的信息有限。在目前的工作中，我们确定了最短的生物活性C端片段ELA23-32，它对APJ具有高亲和力（K i 4.6 nM）并在体内产生心肾作用与ELA类似。对保守残基（Leu25，His26，Val29，Pro30，Phe31，Pro32）的SAR研究表明，ELA和apelin-13与APJ的相互作用可能不同。His26和Val29对于ELA结合显得很重要。对接和结合实验表明，ELA的Phe31可能与不同于Ape13的Phe13的紧密凹槽结合，而Phe13的口袋可能被ELA的Pro32占据。对Gα信令型材的进一步表征I1，Gα 12，和β-arrestin2的途径揭示了芳族残基的受体活化的Phe31或Pro32位置的重要性。
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