CstF-64T Inhibitors

Chemical inhibitors of CstF-64T can interfere with the protein's function by targeting the processes that are integral to its activity. Cordycepin, for example, mirrors adenosine in structure and acts as a chain terminator during mRNA synthesis. The incorporation of cordycepin into the growing RNA chain halts further elongation, which in turn prevents the maturation of pre-mRNA, a process that requires the action of CstF-64T for 3' end cleavage and polyadenylation. Similarly, α-Amanitin exerts its inhibitory effects by binding to and incapacitating RNA polymerase II, the enzyme responsible for transcribing mRNA. This results in a substantial decrease in the pool of nascent pre-mRNA available for further processing by CstF-64T. On the same lines, DRB and Flavopiridol inhibit cyclin-dependent kinases like CDK9 and CDK7, which are vital for the phosphorylation of RNA polymerase II, a necessary step for transcriptional elongation. The consequent reduction in mRNA transcription indirectly restricts the activity of CstF-64T.

Further, Triptolide non-selectively obstructs transcriptional activity by hindering transcription factors, thus diminishing the synthesis of pre-mRNA substrates necessary for CstF-64T function. Mycophenolic Acid, through its inhibition of inosine monophosphate dehydrogenase, leads to a depletion of guanine nucleotides, which are essential for RNA synthesis, and therefore, indirectly impairs the function of CstF-64T. Actinomycin D and Distamycin A disrupt the transcription initiation complex and transcription factor binding to DNA, respectively, which results in a decreased production of mRNA for CstF-64T to act upon. Camptothecin's inhibition of DNA topoisomerase I limits the availability of relaxed DNA, which is required for transcription, and as a result, for CstF-64T activity. Additionally, α-Sarcin and Ricin induce cellular stress responses that can lead to a reduction in transcription and RNA processing, thus indirectly reducing CstF-64T function. Lastly, Homoharringtonine inhibits protein synthesis, which can cause cellular stress responses that potentially downregulate RNA processing pathways, including those involving CstF-64T. Each of these chemicals, by disrupting specific stages of mRNA synthesis and processing, can functionally inhibit the activity of CstF-64T.