RNA-dependent RNA polymerase (RdRp) is an enzyme fundamental to the life cycles of many viruses. It synthesizes new RNA strands using an existing RNA molecule as a blueprint. This enzymatic activity is distinct from processes typically found in human cells, which primarily use DNA as a template for RNA synthesis.
The Central Role of RdRp
RdRp creates new RNA molecules directly from an RNA template. This process, known as RNA replication or transcription, involves the enzyme catalyzing the formation of phosphodiester bonds between ribonucleotides. The enzyme positions itself on the template RNA strand and recruits individual nucleotide building blocks. These nucleotides are then added one by one, complementary to the template, forming a new RNA chain.
RNA synthesis can begin in two primary ways: either without a primer (de novo initiation) or with the help of a small initiating molecule called a primer (primer-dependent). Once initiated, the RdRp moves along the template, extending the new RNA strand in a specific direction. This elongation continues until the entire template is copied, resulting in a newly synthesized RNA molecule.
Where RdRp is Found
RNA-dependent RNA polymerase is predominantly found in RNA viruses. It is an essential component of their replication machinery, enabling these viruses to multiply within host cells. Examples include coronaviruses like SARS-CoV-2, influenza viruses, hepatitis C virus, and poliovirus.
RdRp is generally absent in most eukaryotic cells, including human cells. This absence makes viral RdRp a distinct enzyme within an infected organism. Some eukaryotes possess RdRps, but these function in processes like RNA interference and differ structurally from their viral counterparts.
Why RdRp is Unique and Important for Viruses
RdRp is unique because most cellular organisms, including humans, do not possess enzymes that synthesize RNA directly from an RNA template. Cellular life uses DNA as the genetic blueprint, with DNA-dependent RNA polymerases transcribing DNA into RNA. Viruses with RNA genomes require their own specialized machinery to replicate their genetic material.
This enzyme is necessary for the survival and propagation of RNA viruses. Without RdRp, these viruses cannot copy their RNA genomes, halting their life cycle and preventing new viral particle production. RdRp allows RNA viruses to bypass host cell’s normal DNA-centric replication mechanisms, enabling their unique replication strategy. The high error rate of many viral RdRps, due to a lack of proofreading, also contributes to rapid evolution and adaptability.
RdRp as a Target for Antiviral Therapies
The uniqueness and essential function of RdRp in RNA viruses make it a promising target for antiviral drug development. Since human cells lack this enzyme, drugs that specifically inhibit RdRp are less likely to interfere with normal cellular processes, leading to fewer side effects. Targeting RdRp can effectively halt viral replication without broadly disrupting host cell functions.
Antiviral drugs targeting RdRp often interfere with its ability to synthesize RNA. One common mechanism involves nucleoside analogs, which mimic RNA’s natural building blocks. When incorporated into the growing RNA strand by RdRp, these analogs can cause premature termination or introduce errors, stopping viral replication. Examples include remdesivir (for SARS-CoV-2) and sofosbuvir (for Hepatitis C virus). Other inhibitors bind to different sites on the enzyme, altering its shape or function and preventing it from working correctly.