RNA-dependent RNA polymerase (RdRp) inhibitors: The current landscape and repurposing for the COVID-19 pandemic

Abstract

The widespread nature of several viruses is greatly credited to their rapidly altering RNA genomes that enable the infection to persist despite challenges presented by host cells. Within the RNA genome of infections is RNA-dependent RNA polymerase (RdRp), which is an essential enzyme that helps in RNA synthesis by catalysing the RNA template-dependent development of phosphodiester bonds. Therefore, RdRp is an important therapeutic target in RNA virus-caused diseases, including SARS-CoV-2. In this review, we describe the promising RdRp inhibitors that have been launched or are currently in clinical studies for the treatment of RNA virus infections. Structurally, nucleoside inhibitors (NIs) bind to the RdRp protein at the enzyme active site, and nonnucleoside inhibitors (NNIs) bind to the RdRp protein at allosteric sites. By reviewing these inhibitors, more precise guidelines for the development of more promising anti-RNA virus drugs should be set, and due to the current health emergency, they will eventually be used for COVID-19 treatment.

Keywords: COVID-19; Nucleoside/non-nucleoside analogue inhibitor; RNA virus; RNA-dependent RNA polymerase (RdRp); SARS-CoV-2.

Graphical abstract

Fig. 1

Domain organization of SARS-CoV-2 nsp 12 (RdRp). The interdomain borders are labelled with residue numbers. RdRp: RNA-dependent RNA polymerase.

Fig. 2

Structure of RdRps of positive-strand RNA viruses. A: poliovirus 3Dpol (1RDR); B: HCV NS5B polymerase (1NB4); and C: nsp 12-nsp7-nsp8 complexes of SARS-CoV-2 (7BW4). Nsp7 and nsp8 act as cofactors to promote the activity of RdRp (grey). The palm, finger and thumb subdomains are shown in purple, green and yellow, respectively. RdRp: RNA-dependent RNA polymerase.

Fig. 3

Domain organization of the L protein of vesicular stomatitis virus. The conserved regions within L proteins of nonsegmented negative-strand RNA viruses are labelled CR I–VI.

Fig. 4

Structure of the RdRp domain of nonsegmented negative-strand RNA virus polymerases. A: Vesicular stomatitis virus L protein (5A22); B: respiratory syncytial virus protein L protein (6UEN); and C: rotavirus VP1 protein (2R7Q). The palm, finger and thumb subdomains are shown in purple, green and yellow, respectively. RdRp: RNA-dependent RNA polymerase.

Fig. 5

Structures of nucleoside analogue inhibitors.

Fig. 6

Structures of nonnucleoside analogue inhibitors.

Fig. 7

Structure of the RdRp inhibitor repurposing for the COVID-19 pandemic.

Fig. 8

Structure of the antibacterial drugs that have potential inhibitory interactions with RdRp of SARS-CoV-2.

Fig. 9

The interaction of SRAS-CoV-2 RdRp with (a) ZINC09128258 and (b) ZINC09883305. Solid blue lines represent H-bonds, while hydrophobic interactions are grey dashed lines. In addition, π-cation stacking is represented by yellow spheres connected by dashed lines.