Nucleoside and nucleotide analogues

Nucleoside analogues are the oldest class of antiviral drugs. They date back to the 1960ies, when vidarabine, an adenosine nucleoside analogue, was approved for systemic treatment of herpes virus infections. Nucleotides are building blocks of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) consisting of a five-carbon sugar (deoxyribose or ribose) with an attached phosphate group and a variable nucleobase. There are two purine nucleobases (adenine and guanine) and two pyrimidine nucleobases (cytosine and uracil (RNA) / thymine (DNA)). Nucleosides cannot be used to synthesise nucleic acid polymers as they lack the essential phosphate group. Nucleotides can be created from nucleosides through phosphorylation, an enzymatic reaction in which a phosphate group is attached to the nucleoside. Therefore, nucleotides are also called nucleoside monophosphate, nucleoside diphosphate or nucleoside triphosphate depending on the number of attached phosphate groups.

Nucleoside and nucleotide analogues have modified nucleobases and/or sugar components. They function by mimicking naturally occurring nucleosides/nucleotides. This distinction is between nucleoside and nucleotide analogues is irrelevant for the mechanism of action as both undergo various intracellular enzymatic reactions resulting in phosphorylated pharmacologically active metabolites. These metabolites bind to and inhibit enzymes such as viral and/or human DNA polymerases or viral reverse transcriptase. They may be incorporated into RNA and DNA strands leading to chain termination and may cause the formation of faulty nucleic acids and proteins and subsequently, cellular apoptosis. Nucleos(t)ide analogues inhibiting human DNA polymerases are used as anti-cancer drugs. Antiviral nucleos(t)ide analogues are specific to viral enzymes with limited effects on healthy human cells.
Ribavirin is a guanosine analogue with various proposed mechanisms of action including the inhibition of viral mRNA capping and enhancement of viral mutagenesis. Resistances to nucleos(t)ide analogues oftendevelop rapidly and may be mediated by mutations of viral DNA polymerases which prevent the incorporation of nucleos(t)ide analogues into the viral DNA strand. Another common mechanism of resistance is mutations affecting viral enzymes involved with the phosphorylation of nucleos(t)ide analogues preventing the creation of pharmacologically active metabolites.

NRTIs are the backbone of antiretroviral therapy in patients living with HIV. Standard regimen is two NRTIs (backbone) and an additional antiretroviral drug of a different class (base). They are also a component of first-line therapy in HIV post-exposure prophylaxis (PEP). Truvada and descovy are commonly prescribed for HIV pre-exposure prophylaxis (PrEP). Some NRTIs are active against hepatitis B by inhibiting the reverse transcriptase activity of HBV polymerase. Neither chronic HBV nor HIV can be cleared by antiviral drug therapy as of today. Ganciclovir/valganciclovir inhibit CMV-specific DNA polymerase. Acyclovir/valacyclovir inhibit HSV-specific and VZV-specific DNA polymerases. Ribavirin and remdesivir have broad-spectrum antiviral activity.

Nucleos(t)ide analogues are prodrugs which only become pharmacologically active after intracellular phosphorylation. Bioavailability varies but may be high as 90% in some drugs but less than 25% in others. Most nucleoside/nucleotide analogues are cleared by the kidneys.

Nucleoside/nucleotide analogues side effects vary greatly. As a general rule, drugs inhibiting specific viral polymerases (e.g., acyclovir) tend to be well-tolerated. Nucleoside/nucleotide analogues have long been suspected to inhibit human mitochondrial DNA polymerase causing toxic effects such as lactic acidosis, myopathy, neutropenia, anaemia, hepatotoxicity and cardiomyopathy. Most drugs of this class may be nephrotoxic. Lipodystrophy with subcutaneous fat loss was frequently seen in patients treated with older thymidine analogues like zidovudine. Newer NRTIs tend to have a more favourable side effect profile.