Viral and host RNA polymerases (RNAP)

RNA polymerases (RNAPs) are a diverse group of enzymes responsible for the synthesis of RNA molecules from DNA or RNA templates, a process fundamental to all life and many viral life cycles (Werner & Grohmann, 2011, Nature Reviews Microbiology). In eukaryotic hosts, DNA-directed RNA polymerases (Pol I, II, and III) catalyze the transcription of nuclear DNA into messenger, ribosomal, and transfer RNAs, which are essential for protein synthesis and cellular function (Kuebel et al., 2022, Cells). Many viruses, particularly RNA viruses, encode their own RNA-dependent RNA polymerases (RdRps) to replicate their genomes and transcribe viral mRNA within the host cell (Arnold et al., 2012, Chemical Reviews). Because viral RdRps often lack a direct human homolog, they are highly attractive targets for antiviral therapy, leading to the development of nucleoside and non-nucleoside inhibitors like remdesivir and sofosbuvir (Pruijssers & Denison, 2019, Journal of Biological Chemistry). Conversely, host RNA polymerase inhibitors, such as lurbinectedin, are utilized in oncology to disrupt the rapid transcription required by malignant cells (Kuebel et al., 2022, Cells). However, achieving selectivity for viral polymerases over host polymerases is a significant challenge, as off-target inhibition can lead to mitochondrial toxicity or systemic side effects (Venkatraman et al., 2019, Journal of Medicinal Chemistry). Additionally, the high mutation rate of viral polymerases often leads to the rapid development of drug resistance, necessitating combination therapies (Arnold et al., 2012, Chemical Reviews).

Other names

RNA polymeraseRNA-dependent RNA polymeraseDNA-directed RNA polymeraseTranscriptaseRdRpDdRPRNA pol

Inhibition of RNA synthesis through nucleoside analog chain termination, competitive binding at the catalytic active site, or allosteric modulation of the enzyme complex to prevent template progression.