RDRP

Fig. 8 Pteridine series of NS5B RdRp active compounds...

Two approaches that have been validated for HIV inhibitors, nucleoside 5 -phosphonates [48] and 1,3-dioxolane analogs [49] have proven unsuccessful when applied to HCV inhibitors. Phosphonodiphosphates have been synthesized and are incorporated by NS5B RdRp, but Vmax/Km for these chain terminators is 10-100-fold less than for ATP, and potency must be greatly improved for analogs of this type to have utility [50]. A small series of 1,3-dioxolanes also failed to afford active inhibitors of HCV, or HIV, despite the addition of a 5-methyl substituent to impose the desired conformational preference [51]. Ring expanded nucleobases [52,53] and AICAR analogs have also been synthesized as HCV inhibitors which provide only weak replicon activity [54]. 

Fig. 2 The RNAi mechanisms. In the cytoplasm, dsRNA is cleaved into 22nt fragments called small interfering RNAs (siRNAs) by the RNase III t5rpe enzyme Dicer. The siRNAs are unwound and serve either as primers for RdRP (left) in some taxa (e.g., plants and nematodes) or, more universally, as guide strand in the RISC (right). RdRP creates additional dsRNA, amplifying the substrate for Dicer. RISC cleaves the target RNA in the region bound by the siRNA guide.

Systemic RNAi requires RdRP-mediated amplification to produce sufficient trigger for silencing throughout the organism. In addition, it requires a system for transport of the silencing signal across cell membranes. ... 

RdRp (NS5B) binds to promoter sequence 3rX tail ) at 3 end of the genomic RNA... 

RdRp binds to promoter sequence at the 3 end of the <-) strand progeny RNA... 

Fig. 1. Model for HCV RNA replication. The diagram shows the putative formation and function of the HCV replication complex that involves the RNA-dependent RNA polymerase (RdRp) together with the NS3/4A multifunctional enzyme. The RdRp catalyzes the formation of phosphodiester bonds between adjacent nucleotides, and the helicase separates the two RNA strands after synthesis.

Nematode viruses. It was not easy to recognize viral pathogens of C. elegans (Figure 39). The laboratory strains of C. elegans probably were virus-free (if not, some conclusions of basic research may have to be revised). The positive RNA strand Nodaviruses infect the nematodes. The viral genome encodes its own RdRp. 

Currently, three categories of anti-HCV DAAs have been approved, and the nomenclature is based on which viral function is inhibited or affected. The categories are NS3/NS4A protease inhibitors [PI, e.g., boceprevir (2), telaprevir (3), and simeprevir (4)], NS5A protein inhibitors [e.g., ledipasvir (5)], and NS5B RNA-dependent RNA polymerase (RdRp) inhibitors (e.g., sofosbuvir). The last category can be divided further into two subclasses nucleoside/nucleotide polymerase inhibitors (NPI) and nonnucleoside polymerase inhibitors (NNPI). 

The HCV NS5B RNA-dependent RNA polymerase (RdRp) catalyzes de novo RNA synthesis requiring a template and substrate nucleotide triphosphates, and does not contain a proofreading function. Nucleoside/nucleotide polymerase inhibitors mimic the natural substrates of the polymerase and are incorporated into the RNA chain, causing direct chain termination." ... 

The HCV NS5B gene encodes the viral RNA-dependent RNA polymerase (RdRP) which is responsible for the replication of the viral genome. It is a clinically validated and tractable target of considerable interest. 

N. Verdaguer and C. Ferrer-Orta, Conformational Changes in Motif D of RdRPs as Fidelity Determinant, Structure, 2012, 20,1448. 

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