In search of a small molecule agonist of the relaxin receptor RXFP1 for the treatment of liver fibrosis.
In search of a small molecule agonist of the relaxin receptor RXFP1 for the treatment of liver fibrosis.
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DOI：
10.1038/s41598-017-10521-9
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发表时间：
2017-09-07
影响因子：
4.6
通讯作者：
Fallowfield JA
中科院分区：
文献类型：
--
作者：
McBride A;Hoy AM;Bamford MJ;Mossakowska DE;Ruediger MP;Griggs J;Desai S;Simpson K;Caballero-Hernandez I;Iredale JP;Pell T;Aucott RL;Holmes DS;Webster SP;Fallowfield JA
肽激素人松弛素-2 （H2-RLX）已成为心血管和纤维化疾病的潜在治疗方法，但其体内半衰期短是长期给药的障碍。ML290的发现证明了鉴定H2-RLX同源g蛋白偶联受体（松弛素家族肽受体-1 (RXFP1)）的小分子激动剂是可能的。在我们努力开发一种治疗肝纤维化的新药的过程中，我们试图鉴定具有选择性、完全激动剂或阳性变张力调节剂活性的H2-RLX的改进小分子功能模拟物。首先，我们证实了RXFP1在人患病肝脏中的表达。我们在瞬时表达RXFP1的HEK293细胞中建立了一种强大的细胞cAMP报告实验。高通量筛选未发现RXFP1的进一步特异性激动剂或阳性变构调节剂，证实了该受体的低药物性。作为一种替代方法，我们生成了新的ML290类似物，并在HEK293-RXFP1 cAMP实验和人肝细胞系LX-2中测试了它们的活性。与纤维化标记物表达变化相比，cAMP激活化合物活性的差异表明，需要更好地了解细胞和组织特异性信号机制及其疾病相关表型，以便发现药物。
The peptide hormone human relaxin-2 (H2-RLX) has emerged as a potential therapy for cardiovascular and fibrotic diseases, but its short in vivo half-life is an obstacle to long-term administration. The discovery of ML290 demonstrated that it is possible to identify small molecule agonists of the cognate G-protein coupled receptor for H2-RLX (relaxin family peptide receptor-1 (RXFP1)). In our efforts to generate a new medicine for liver fibrosis, we sought to identify improved small molecule functional mimetics of H2-RLX with selective, full agonist or positive allosteric modulator activity against RXFP1. First, we confirmed expression of RXFP1 in human diseased liver. We developed a robust cellular cAMP reporter assay of RXFP1 signaling in HEK293 cells transiently expressing RXFP1. A high-throughput screen did not identify further specific agonists or positive allosteric modulators of RXFP1, affirming the low druggability of this receptor. As an alternative approach, we generated novel ML290 analogues and tested their activity in the HEK293-RXFP1 cAMP assay and the human hepatic cell line LX-2. Differences in activity of compounds on cAMP activation compared with changes in expression of fibrotic markers indicate the need to better understand cell- and tissue-specific signaling mechanisms and their disease-relevant phenotypes in order to enable drug discovery.
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影响因子：
16.6
作者：
Lopez-Sanchez, Inmaculada;Lopez-Sanchez, Inmaculada;Dunkel, Ying;Roh, Yoon-Seok;Mittal, Yash;De Minicis, Samuele;Muranyi, Andrea;Singh, Shalini;Shanmugam, Kandavel;Aroonsakool, Nakon;Murray, Fiona;Ho, Samuel B.;Seki, Ekihiro;Brenner, David A.;Ghosh, Pradipta
通讯作者：
Ghosh, Pradipta
影响因子：
8.4
作者：
Hossain MA;Kocan M;Yao ST;Royce SG;Nair VB;Siwek C;Patil NA;Harrison IP;Rosengren KJ;Selemidis S;Summers RJ;Wade JD;Bathgate RAD;Samuel CS
通讯作者：
Samuel CS
影响因子：
4.8
作者：
Mookerjee, Ishanee;Hewitson, Tim D.;Samuel, Chrishan S.
通讯作者：
Samuel, Chrishan S.
影响因子：
--
作者：
Chen CZ;Southall N;Xiao J;Marugan JJ;Ferrer M;Hu X;Jones RE;Feng S;Agoulnik IU;Zheng W;Agoulnik AI
通讯作者：
Agoulnik AI
DOI：
10.1111/liv.12247
发表时间：
2014-03
期刊：
Liver international : official journal of the International Association for the Study of the Liver
影响因子：
--
作者：
Bennett RG;Heimann DG;Singh S;Simpson RL;Tuma DJ
通讯作者：
Tuma DJ