DHX33 Inhibitors

Chemical inhibitors of DHX33 include a variety of compounds that target different aspects of its enzymatic activity, primarily focusing on the ATPase and RNA helicase functions. Adenosine 5'-triphosphate disodium can directly compete for ATP binding sites on DHX33, which are indispensable for the protein's helicase activity. By occupying these sites, the compound effectively inhibits the ATPase function critical for the unwinding of RNA substrates, a primary role of DHX33. Similarly, Enoxacin and Flavopiridol attack the same ATPase domain, with Enoxacin directly interfering with ATP hydrolysis and Flavopiridol binding to the ATP-binding pocket. Both mechanisms result in the inhibition of DHX33's ability to manipulate RNA structures, which is necessary for its role in RNA metabolism.

Additionally, Aurintricarboxylic acid inhibits DHX33 by a different mechanism, blocking the protein's ability to bind RNA, which is a prerequisite for helicase activity. This binding is also impeded by Myricetin, which intercalates with the RNA substrate, preventing DHX33 from accessing the RNA it needs to unwind. Nucleotide analogs like 5'-Guanylyl imidodiphosphate and Ribavirin interfere with the GTP binding and hydrolysis, with 5'-Guanylyl imidodiphosphate serving as a non-hydrolyzable GTP analog and Ribavirin mimicking guanosine nucleotides, both leading to an inhibition of the GTPase activity essential for DHX33 function. On the other hand, compounds like 2'-Deoxyadenosine 5'-triphosphate and 7-Deazaadenosine compete with ATP, which is indispensable for the catalytic action of DHX33's helicase domain, thereby inhibiting its function. Lastly, general ATPase inhibitors like Suramin and Sodium orthovanadate nonspecifically obstruct the ATP binding required for enzymatic activity, while BX-795, although primarily a kinase inhibitor, blocks the ATP binding site crucial for DHX33's helicase action. Each of these chemicals acts to inhibit the enzymatic activity of DHX33, thereby inhibiting the protein's function in RNA processing and metabolism.