Viral RNA-dependent RNA polymerase and nucleotide biosynthetic pathways (RdRp/NTP pools)

The viral RNA synthesis machinery, primarily centered on the RNA-dependent RNA polymerase (RdRp), is the essential engine for the replication and transcription of RNA virus genomes (Source: PubMed, PMID: 32733101). This machinery is highly dependent on the availability of host nucleotide pools, specifically ribonucleoside triphosphates (NTPs), which serve as the building blocks for new viral RNA strands (Source: Nature Reviews Drug Discovery, 2020). Therapeutic strategies targeting this system include the use of nucleoside analogs that act as chain terminators or induce lethal mutagenesis, as well as host-targeted inhibitors of enzymes like dihydroorotate dehydrogenase (DHODH) to deplete the nucleotide supply (Source: Science Signaling, 2020). Because RdRp is a viral-specific enzyme with no direct human ortholog, it represents a high-priority target for broad-spectrum antiviral development (Source: NIH, NIAID). However, drug design must carefully avoid interfering with host mitochondrial or nuclear polymerases to minimize toxicity.

Other names

Viral RNA synthesis machineryViral replicase complexRNA-dependent RNA polymerase (RdRp)Nucleotide metabolismPurine and pyrimidine biosynthesis pathways

Drugs targeting this system work through two primary modalities: direct inhibition of the viral RNA-dependent RNA polymerase (RdRp) and modulation of the substrate supply. Nucleoside/nucleotide analogs (e.g., Remdesivir, Sofosbuvir) act as prodrugs that are phosphorylated intracellularly to their active triphosphate forms; these then compete with endogenous nucleotides for incorporation into the nascent RNA strand, leading to chain termination or lethal mutagenesis (Source: PubMed, PMID: 32454408). Alternatively, host-targeted inhibitors (e.g., DHODH inhibitors) block the de novo synthesis of pyrimidines, reducing the intracellular nucleotide pools to levels that cannot sustain rapid viral replication (Source: Journal of Virology, 2021).