在色素性视网膜炎小鼠模型中发现抑制错误折叠视紫红质致病作用的非类视黄醇化合物。

IF 9.8 1区 生物学 Q1 Agricultural and Biological Sciences
PLoS Biology Pub Date : 2025-01-14 eCollection Date: 2025-01-01 DOI:10.1371/journal.pbio.3002932
Joseph T Ortega, Jacklyn M Gallagher, Andrew G McKee, Yidan Tang, Miguel Carmena-Bargueňo, Maria Azam, Zaiddodine Pashandi, Marcin Golczak, Jens Meiler, Horacio Pérez-Sánchez, Jonathan P Schlebach, Beata Jastrzebska
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引用次数: 0

摘要

致病性突变导致视紫红质错误折叠导致一系列目前无法治疗的致盲疾病,统称为色素性视网膜炎。因此,迫切需要小分子来纠正视紫红质错误折叠。在这项研究中,我们利用虚拟筛选来寻找与杆状视蛋白正位位点结合并改善其折叠和运输的药物样分子。我们鉴定并验证了2种非类视黄醇化合物的生物学效应,这些化合物具有良好的药理特性,可以穿过血液-视网膜屏障。这些化合物可逆地与无配体视蛋白结合,每个化合物的Kd与9-顺式视网膜相当,并提高视蛋白的稳定性。通过改善内部蛋白结构网络(PSN),这些杆状视蛋白配体也增强了123个临床RP变异中的36个的质膜表达,包括最常见的P23H变异。重要的是,这些化合物保护易受强光损伤小鼠的视网膜免受光诱导变性,并延长视网膜色素变性小鼠模型中视蛋白错误折叠的光感受器的存活时间。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Discovery of non-retinoid compounds that suppress the pathogenic effects of misfolded rhodopsin in a mouse model of retinitis pigmentosa.

Pathogenic mutations that cause rhodopsin misfolding lead to a spectrum of currently untreatable blinding diseases collectively termed retinitis pigmentosa. Small molecules to correct rhodopsin misfolding are therefore urgently needed. In this study, we utilized virtual screening to search for drug-like molecules that bind to the orthosteric site of rod opsin and improve its folding and trafficking. We identified and validated the biological effects of 2 non-retinoid compounds with favorable pharmacological properties that cross the blood-retina barrier. These compounds reversibly bind to unliganded rod opsin, each with a Kd comparable to 9-cis-retinal and improve opsin stability. By improving the internal protein structure network (PSN), these rod opsin ligands also enhanced the plasma membrane expression of total 36 of 123 tested clinical RP variants, including the most prevalent P23H variant. Importantly, these compounds protected retinas against light-induced degeneration in mice vulnerable to bright light injury and prolonged survival of photoreceptors in a retinitis pigmentosa mouse model for rod opsin misfolding.

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来源期刊
PLoS Biology
PLoS Biology BIOCHEMISTRY & MOLECULAR BIOLOGY-BIOLOGY
CiteScore
15.40
自引率
2.00%
发文量
359
审稿时长
3-8 weeks
期刊介绍: PLOS Biology is the flagship journal of the Public Library of Science (PLOS) and focuses on publishing groundbreaking and relevant research in all areas of biological science. The journal features works at various scales, ranging from molecules to ecosystems, and also encourages interdisciplinary studies. PLOS Biology publishes articles that demonstrate exceptional significance, originality, and relevance, with a high standard of scientific rigor in methodology, reporting, and conclusions. The journal aims to advance science and serve the research community by transforming research communication to align with the research process. It offers evolving article types and policies that empower authors to share the complete story behind their scientific findings with a diverse global audience of researchers, educators, policymakers, patient advocacy groups, and the general public. PLOS Biology, along with other PLOS journals, is widely indexed by major services such as Crossref, Dimensions, DOAJ, Google Scholar, PubMed, PubMed Central, Scopus, and Web of Science. Additionally, PLOS Biology is indexed by various other services including AGRICOLA, Biological Abstracts, BIOSYS Previews, CABI CAB Abstracts, CABI Global Health, CAPES, CAS, CNKI, Embase, Journal Guide, MEDLINE, and Zoological Record, ensuring that the research content is easily accessible and discoverable by a wide range of audiences.
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