RdRp (RNA-dependent RNA polymerase): A key target providing anti-virals for the management of various viral diseases

Abstract

With the arrival of the Covid-19 pandemic, anti-viral agents have regained center stage in the arena of medicine. Out of the various drug targets involved in managing RNA-viral infections, the one that dominates almost all RNA viruses is RdRp (RNA-dependent RNA polymerase). RdRp are proteins that are involved in the replication of RNA-based viruses. Inhibition of RdRps has been an integral approach for managing various viral infections such as dengue, influenza, HCV (Hepatitis), BVDV, etc. Inhibition of the coronavirus RdRp is currently rigorously explored for the treatment of Covid-19 related complications. So, keeping in view the importance and current relevance of this drug target, we have discussed the importance of RdRp in developing anti-viral agents against various viral diseases. Different reported inhibitors have also been discussed, and emphasis has been laid on highlighting the inhibitor's pharmacophoric features and SAR profile.

Template Entrance Channel as Possible Allosteric Inhibition and Resistance Site for Quinolines Tricyclic Derivatives in RNA Dependent RNA Polymerase of Bovine Viral Diarrhea Virus

“…Although no clear evidence for the role of this domain has been reported yet, it is believed that the N-terminal, along with the fingertip region, forms the template entrance channel [ 31 , 32 ]. The flexibility of loop L4 (linker) of N-terminal regions is very important for template translocation during polymerization [ 4 , 9 ]. The fingertip domain is believed to be involved in the template/product translocation, dimerization of RdRp within the Replication Complex (RC), or protein–protein interactions, enabling the assembly of an active RC [ 22 , 30 ].…”

“…With this aim, a promising option is the use of non-nucleoside inhibitors (NNIs), that specifically target the active form of BVDV RdRp, which is differentiated by the positioning of linker and hood ( Figure 1 A,B) [ 4 , 8 ]. Following this route, some selective anti-BVDV inhibitors have been discovered [ 2 , 5 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. However, the molecular recognition of BVDV RdRp with allosteric NNIs has not been extensively studied, as no co-crystallized NNI-RdRp has been published to our knowledge.…”

Revisiting Viral RNA-Dependent RNA Polymerases: Insights from Recent Structural Studies

“…For example, the re-association of the 3′ template RNA at the polymerase surface of FluA following exit protected it against nucleases [ 77 ], and the interactions of the NTDs of the pestiviral RdRPs promoted the unwinding of the RNA duplex [ 65 ]. The varied nature of the inhibitor binding pockets of RdRPs from distinct viruses necessitates the search for antivirals with unique pharmacophoric properties [ 14 , 98 ]. For example, the benzofuran-, thiazolidinone-, or anilinobenzothiazole-derived inhibitors were effective against HCV, while pyrazole or bibenzylsubstituted piperazine-containing compounds performed well against Zika and the octahydroquinazoline derivatives strongly inhibited DENV RdRP.…”

Nanotechnology-Based RNA Vaccines: Fundamentals, Advantages and Challenges

“…Self-amplifying RNA also contains open reading frames encoding the components of RNA-dependent RNA polymerases (RDRP). RDRPs are used by RNA viruses for amplification of RNA [ 117 ]. Utilizing such a pathway in RNA-based vaccines multiplies the number of RNA copies in the host cell increasing the production of antigens.…”