NSUN1 Inhibitors

Chemical inhibitors of NSUN1 function by various mechanisms to impede its catalytic activity, essential for RNA methylation. The presence of 5-azacytidine in RNA acts as a potent inhibitor by becoming incorporated into RNA and subsequently trapping NSUN1 in a covalent complex, which obstructs further enzymatic activity. Similarly, N6-Methyladenosine competes with the natural substrate of NSUN1, binding to the enzyme's active site and thereby preventing access to the actual substrates. Another approach is the utilization of nucleoside analogs, such as Decitabine and Zebularine, which upon incorporation into RNA, can block the RNA-binding site of NSUN1, disrupting the methylation process.

Additional inhibitors, such as RG108, Sinefungin, and Aurintricarboxylic acid, operate by directly or indirectly binding to NSUN1 or its substrate. RG108, although primarily a DNA methyltransferase inhibitor, could affect the RNA methylation landscape and thus interfere with NSUN1's activity. Sinefungin acts as a universal methyltransferase inhibitor, likely occupying the catalytic site of NSUN1 and blocking substrate binding. Aurintricarboxylic acid is known to inhibit various nucleic acid enzymes and could impede NSUN1 by non-specifically binding to its active site or RNA substrate. Mithramycin A, which binds to G-C rich DNA sequences, may influence the transcription of RNA, reducing the availability of substrates for NSUN1 to methylate. BIX-01294 and Chaetocin, both histone methyltransferase inhibitors, might exert an indirect effect on NSUN1 by changing the chromatin structure, affecting the transcription of RNA substrates required by NSUN1. Lastly, Quercetin, a kinase inhibitor, can impact NSUN1 activity by altering the phosphorylation states that regulate NSUN1 function, thereby modulating its activity without directly binding to the enzyme or the RNA substrate.