Chemical biology and medicinal chemistry of RNA methyltransferases

Abstract

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.

Experience with German Research Consortia in the Field of Chemical Biology of Native Nucleic Acid Modifications

“…Therefore, an explicit goal of the SPP was to elucidate the structure and dynamics of modification enzymes and their nucleic acid substrates before, during, and after a catalytic modification event. Certain aspects of biological chemistry, that had been explicitly mentioned as a component of the SPP1784, included the development of cofactor analogs as tool compounds, as inhibitors of modification reactions, for crystallographic studies, or as probes . The interaction of such small molecules was to be characterized enzymologically and accompanied by structural biology, where appropriate.…”

“…Certain aspects of biological chemistry, that had been explicitly mentioned as a component of the SPP1784, included the development of cofactor analogs as tool compounds, as inhibitors of modification reactions, for crystallographic studies, or as probes. 46 The interaction of such small molecules was to be characterized enzymologically and accompanied by structural biology, where appropriate. The evidence generated in this regard during the grant period is too extensive to even mention all of the high-level publications.…”

Functional integration of a semi-synthetic azido-queuosine derivative into translation and a tRNA modification circuit

“…propargyl residues, has enabled their incorporation into RNA in lieu of methyl groups. Subsequent derivatization by click chemistry was exploited for determination of modification sites ( 75 , 76 , 66 ).…”

Chemical Space Virtual Screening against Hard-to-Drug RNA Methyltransferases DNMT2 and NSUN6

“…One prominent example of interfering with RNA modifying enzymes as a therapeutic strategy is the methyltransferase 3 (METTL3, also called N 6 -adenosine-methyltransferase) inhibitor STM2457, which is under investigation for the treatment of acute myeloid leukemia (AML) [ 8 ]. Examination of other RNA methyltransferases as possible drug targets is still in its infancy, which is also reflected in the literature [ 9 ]. However, in recent times, research in this area has started to accelerate.…”