Nucleoside Analogues in Antimicrobial and Antiviral Therapeutics

Nucleoside analogues are synthetic derivatives of natural nucleosides that interfere with nucleic acid metabolism in pathogens. By mimicking the structure of ribo- or deoxyribonucleosides, these compounds can be incorporated into viral or bacterial genomes, leading to chain termination or lethal mutagenesis. Many analogues require intracellular phosphorylation by host or microbial kinases to form active mono-, di- and triphosphate species, which inhibit viral polymerases or key enzymes of bacterial nucleotide salvage pathways. Clinically important examples include inhibitors of HIV reverse transcriptase, hepatitis C virus polymerase and Mycobacterium tuberculosis adenosine kinase. Prodrug strategies, such as phosphoramidate and ester masking, have enhanced oral bioavailability and selective delivery. Resistance emerges through mutations in polymerase active sites or alterations in kinase specificity, prompting continual chemical optimisation. Beyond direct-acting effects, certain analogues potentiate radiotherapy or synergise with other antimicrobials. The global burden of viral epidemics and drug-resistant mycobacterial infections underscores the significance of this class. Ongoing research seeks to expand the chemical diversity of nucleoside scaffolds, improve host tolerance and overcome resistance, thereby broadening the therapeutic repertoire against emerging and re-emerging infectious threats.

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Nucleoside Analogues in Antimicrobial and Antiviral Therapeutics publication trend

The graph below shows the total number of articles in nucleoside analogues in antimicrobial and antiviral therapeutics across all publications each year (not limited to Nature Index journals).

Technical terms

Nucleoside analogue: A synthetic compound structurally similar to a natural nucleoside, designed to disrupt nucleic acid synthesis.

Prodrug: An inactive derivative that undergoes enzymatic or chemical conversion in vivo to release the active drug.

Polymerase: An enzyme that catalyses the synthesis of DNA or RNA strands from nucleotide substrates.

Adenosine kinase: A kinase that phosphorylates adenosine to adenosine monophosphate, activating certain nucleoside analogues.

Chain termination: A mechanism by which an incorporated analogue lacks a 3′-hydroxyl group, preventing further strand elongation.

Purine salvage pathway: A metabolic route in which cells recycle purine bases and nucleosides to form new nucleotides.

References

1. Discovery of 2,9-diaryl-6-carbamoylpurines as a novel class of antitubercular agents. European Journal of Medicinal Chemistry (2024).
2. Pyrrolo[2,3‐d]pyrimidine (7‐deazapurine) as a privileged scaffold in design of antitumor and antiviral nucleosides. Medicinal Research Reviews (2017).
3. Synthesis of Pyrimidine Conjugates with 4-(6-Amino-hexanoyl)-7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine and Evaluation of Their Antiviral Activity. Molecules (2022).
4. New insights into the synergism of nucleoside analogs with radiotherapy. Radiation Oncology (2013).