Chemical biology and medicinal chemistry of RNA methyltransferases.
Chemical biology and medicinal chemistry of RNA methyltransferases.
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DOI：
10.1093/nar/gkac224
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发表时间：
2022-05-06
影响因子：
14.9
通讯作者：
Helm, Mark
中科院分区：
文献类型：
--
作者：
Fischer, Tim R.;Meidner, Laurenz;Schwickert, Marvin;Weber, Marlies;Zimmermann, Robert A.;Kersten, Christian;Schirmeister, Tanja;Helm, Mark
RNA甲基转移酶(MTase)是一种普遍存在的酶，其在药物化学中的地位一直很低，相比之下，人们对RNA甲基化的兴趣与日俱增，RNA甲基化是表位转录组学新领域中最重要的方面。随着MTase被证实为生物医学所有主要领域的药物靶标，作为工具和抑制剂的小分子化合物的开发在学术界和生物技术领域都有相当大的势头。在这里，我们讨论化学生物学两个相关方面的小分子的发展。首先，普遍存在的辅因子S-腺苷-L-蛋氨酸的衍生物正在被开发为生物偶联工具，用于将官能团和标记靶向转移到越来越明显的靶标上。其次，人们正在研究SAM衍生化合物作为RNA MTase抑制剂的能力。药物开发正在从共底物的衍生物转向更高一代的化合物，这些化合物除了催化中心外，还可能涉及变构中心。药物化学在分析开发和筛选技术方面的进展导致了最近的突破，例如在解决人类酶在癌症中的作用方面取得了突破。在当前大流行的刺激下，针对冠状病毒MTase的新抑制剂以惊人的速度出现，包括一种重新调整用途的药物，目前正在进行临床试验。
RNA methyltransferases (MTases) are ubiquitous enzymes whose hitherto low profile in medicinal chemistry, contrasts with the surging interest in RNA methylation, the arguably most important aspect of the new field of epitranscriptomics. As MTases become validated as drug targets in all major fields of biomedicine, the development of small molecule compounds as tools and inhibitors is picking up considerable momentum, in academia as well as in biotech. Here we discuss the development of small molecules for two related aspects of chemical biology. Firstly, derivates of the ubiquitous cofactor S-adenosyl-l-methionine (SAM) are being developed as bioconjugation tools for targeted transfer of functional groups and labels to increasingly visible targets. Secondly, SAM-derived compounds are being investigated for their ability to act as inhibitors of RNA MTases. Drug development is moving from derivatives of cosubstrates towards higher generation compounds that may address allosteric sites in addition to the catalytic centre. Progress in assay development and screening techniques from medicinal chemistry have led to recent breakthroughs, e.g. in addressing human enzymes targeted for their role in cancer. Spurred by the current pandemic, new inhibitors against coronaviral MTases have emerged at a spectacular rate, including a repurposed drug which is now in clinical trial.
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DOI：
10.3390/molecules25184154
发表时间：
2020-09-11
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Boonyasuppayakorn S;Saelee T;Visitchanakun P;Leelahavanichkul A;Hengphasatporn K;Shigeta Y;Huynh TNT;Chu JJH;Rungrotmongkol T;Chavasiri W
通讯作者：
Chavasiri W
影响因子：
2.8
作者：
Ahmed-Belkacem, Rostom;Ortiz, Priscila Sutto;Debart, Francoise
通讯作者：
Debart, Francoise
影响因子：
6.7
作者：
Ahmed-Belkacem, Rostom;Sutto-Ortiz, Priscila;Debart, Francoise
通讯作者：
Debart, Francoise
影响因子：
7.6
作者：
Barral, K.;Sallamand, C.;Decroly, E.
通讯作者：
Decroly, E.
影响因子：
7.3
作者：
Alvesalo, JKO;Siiskonen, A;Vuorela, PM
通讯作者：
Vuorela, PM