Design and development of therapeutics targeting METTL14-mediated signaling pathways to treat cardiovascular diseases

Cardiovascular disease (CVD) encompasses a group of severe cardiac and vascular disorders with high global prevalence and mortality rates. CVD is characterized by abnormal cell death and inflammation of cardiomyocytes and vascular endothelial cells, involving mutually interconnected pathogenic mechanisms. N6-methyladenosine (m6A) RNA modification has emerged as a key mechanism promoting the progression of CVDs through regulation of gene expression. Among the key mediators, Methyltransferase-like 14 (METTL14)-mediated m6A modification modulates the stability of mRNAs and the processing of pre-miRNAs. We critically discuss recent advances elucidating the function of METTL14 in regulating cardiomyocyte death, which leads to myocardial ischemia/reperfusion injury, heart failure and cardiac fibrosis. In addition, METTL14 promotes endothelial inflammation and atherosclerosis. The long noncoding RNA NEAT1 serves as a central effector integrating the functions of most METTL14 substrates in the pathogenesis of CVD. These analyses on METTL14-mediated signaling pathways highlight METTL14, PHLPP2, TLR4 and NEAT1 as potential therapeutic targets. We thoroughly discuss the structure-based design, binding mechanisms, potency, pharmacokinetic properties and safety of small peptides directly targeting METTL14, and stapled peptides disrupting the interface between METTL3 and METT14 in the catalytic complex. The advantages and limitations of these peptides are compared with METTL3-targeting proteolysis-targeting chimeras (PROTACs), which induce the degradation of both METTL3 and METTL14. Our molecular docking analyses, combined with previous structural biology and medicinal chemistry studies, propose potential binding modes of inhibitors to METTL14, PHLPP1/2, and TLR4. These interdisciplinary discussion reveals various novel concepts in designing the therapeutics to combat METTL14-mediated pathologies.