摘要
近十年来,人们对胆固醇生物合成中间体生物学功能的认识发生了重大变化。特别是甾醇脱氢胆固醇还原酶24 (DHCR24)已成为潜在的药物靶点。抑制DHCR24可导致内源性具有生物活性的代谢物cholesta-5,24-dien-3β-ol (desmosterol)的积累。Desmosterol是一种内源性的肝X受体激动剂(LXR)。LXR是脂质代谢的主要调节因子,并因此参与许多病理生理过程,如炎症、动脉粥样硬化、癌症、糖尿病(DM)、多发性硬化症(MS)、非酒精性脂肪性肝炎(NASH)和病毒感染的进展。到目前为止,在不激活甾醇反应元件结合蛋白(sterol-response element binding proteins, SREBP)的情况下对LXR进行选择性药理靶向,从而促进内源性脂质生物合成的研究还未实现。反过来说,没有选择性LXR受体激动剂利用其有益的激活尚未到达临床。因此,使用DHCR24的有效和选择性抑制剂导致内源性desmosterol的积累是选择性激活LXR的一个有前景的替代策略。在此,我们总结了靶向DHCR24的新型先导结构的现状,包括甾体酶抑制剂(例如,20,25-重氮胆甾醇,SH42)和非甾体支架(例如,胺碘酮,triparanol)。此外,我们解释了DHCR24抑制/LXR激活的分子机制,讨论了可能的治疗应用,并阐明了为什么DHCR24是一个有前景的药物靶点。
关键词: 脱氢胆固醇还原酶24,酶抑制剂,去氨甾醇,肝X受体,炎症缓解,非酒精性脂肪性肝炎。
Current Medicinal Chemistry
Title:Dehydrocholesterol Reductase 24 (DHCR24): Medicinal Chemistry, Pharmacology and Novel Therapeutic Options
Volume: 29 Issue: 23
关键词: 脱氢胆固醇还原酶24,酶抑制剂,去氨甾醇,肝X受体,炎症缓解,非酒精性脂肪性肝炎。
摘要:
During the last decade, the understanding of the biological functions of cholesterol biosynthesis intermediates has changed significantly. Particularly, the enzyme sterol dehydrocholesterol reductase 24 (DHCR24) has taken center stage as a potential drug target. Inhibition of DHCR24 leads to accumulation of the endogenous, biologically active metabolite cholesta-5,24-dien-3β-ol (desmosterol). Desmosterol is an endogenous agonist of the liver X receptor (LXR). LXR is a master regulator of lipid metabolism and, as such, is involved in numerous pathophysiological processes such as inflammation, atherosclerosis, cancer, diabetes mellitus (DM), multiple sclerosis (MS), nonalcoholic steatohepatitis (NASH), and the progression of viral infections. Up to now, selective pharmacological targeting of LXR without activating the sterol-response element binding proteins (SREBP) and thereby boosting endogenous lipid biosynthesis has not been achieved. In turn, no selective LXR receptor agonists leveraging its beneficial activation have yet reached the clinic. Therefore, using potent and selective inhibitors of DHCR24 leading to an accumulation of endogenous desmosterol is a promising alternative strategy for the selective activation of LXR.
Here we summarize the present landscape of novel lead structures for targeting DHCR24, covering steroidal enzyme inhibitors (e.g., 20,25-diazacholesterol, SH42) as well as nonsteroidal scaffolds (e.g., amiodarone, triparanol). Further, we explain the molecular mechanisms of DHCR24 inhibition/LXR activation, discuss possible therapeutic applications, and underpin why DHCR24 is an upcoming promising drug target.
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Cite this article as:
Dehydrocholesterol Reductase 24 (DHCR24): Medicinal Chemistry, Pharmacology and Novel Therapeutic Options, Current Medicinal Chemistry 2022; 29 (23) . https://dx.doi.org/10.2174/0929867328666211115121832
DOI https://dx.doi.org/10.2174/0929867328666211115121832 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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