Viral RNA-dependent RNA polymerase and Reverse transcriptase (RdRp/RT)

Viral RNA-dependent RNA polymerases (RdRps) and reverse transcriptases (RTs) are essential enzymes required for the replication of various viral genomes and are primary targets for antiviral therapy [1][2]. RdRps are utilized by RNA viruses, such as SARS-CoV-2 and Hepatitis C, to catalyze the synthesis of an RNA strand complementary to an RNA template, a process vital for viral genome replication and transcription [1][3]. Reverse transcriptases are used by retroviruses like HIV and pararetroviruses like Hepatitis B to convert their single-stranded RNA genome into double-stranded DNA, which can then be integrated into the host cell's genome [2][4]. These enzymes are highly attractive therapeutic targets because they lack direct functional homologs in human cells, allowing for selective inhibition of viral replication [3]. Therapeutic intervention typically involves nucleoside or nucleotide analogues that act as chain terminators, or non-nucleoside inhibitors that bind to allosteric sites to disrupt enzyme function [3][5]. While highly effective, these enzymes often exhibit high mutation rates, leading to the rapid development of drug resistance, which necessitates the use of combination antiretroviral therapy (cART) or multi-drug regimens [2][5]. Notable safety concerns include mitochondrial toxicity, as some nucleoside analogues can cross-react with human mitochondrial DNA polymerase gamma, leading to side effects such as lactic acidosis and hepatic steatosis [6]. Sources: [1] Venkataraman et al. (2018) Exp Mol Pathol; [2] Hu & Hughes (2012) CSH Perspect Med; [3] De Clercq & Li (2016) Clin Microbiol Rev; [4] NIH/NIAID 'HIV Replication Cycle'; [5] StatPearls 'Antiviral Medications'; [6] Lewis & Dalakas (1995) Nature Medicine.

Other names

RNA-directed RNA polymeraseRNA-dependent DNA polymeraseRTRdRpViral polymeraseRNA nucleotidyltransferase (RNA-directed)

Drugs targeting these enzymes primarily function through two mechanisms: nucleoside or nucleotide analogues (NRTIs/NrtIs) act as competitive inhibitors that are incorporated into the growing nucleic acid chain, leading to premature chain termination; non-nucleoside inhibitors (NNRTIs) bind to allosteric sites, inducing conformational changes that inhibit the enzyme's catalytic activity.