Throughout history, many viral diseases have proven difficult to treat. However, recent research into synthetic drugs has given medical science powerful new tools to combat these pathogens. One particularly promising class of drugs is nucleoside analogs, which have been a focus of ongoing research and development.
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Nucleoside Analogs: An Overview
Nucleoside analogs are chemically modified nucleosides composed of a nucleic acid analog, a sugar, and one to three phosphate groups. These molecules mimic the action of natural nucleosides—adenosine, cytidine, uridine, and guanosine—which serve as essential building blocks for DNA and RNA synthesis and play key roles in cell signaling.
Because nucleoside analogs are hydrophilic, they rely on specialized transporter proteins to reach target sites within the body. Once inside a cell, they undergo phosphorylation by nucleoside kinases, forming nucleoside mono-, di-, and triphosphates, which are then incorporated into viral or cellular DNA/RNA.1
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Function and Types of Nucleoside Analog Drugs
Nucleoside analogs are widely used in antiviral therapy, working by interfering with viral DNA or RNA replication. They achieve this by causing premature DNA chain termination and inducing mutations, typically targeting viral polymerases rather than human enzymes, which makes them well-tolerated by patients.
Beyond antiviral applications, nucleoside analogs are also used in cancer treatment, where they disrupt DNA synthesis in rapidly dividing cancer cells. Closely related compounds, including nucleotide and nucleobase analogs, share similar therapeutic mechanisms.
Nucleoside Analogs as Antiviral Drugs
A significant application of nucleoside analogs is in antiviral therapy. In the late 1980s, acyclovir and zidovudine were the most commonly available drugs in this class. Today, there are 25 approved nucleoside therapies, including:
- Didanosine (HIV)
- Remdesivir (Ebola, Coronavirus)
- Entecavir (Hepatitis B)
- Abacavir (HIV)
- Galidesivir (Ebola)
- Idoxuridine (Herpes)
- Trifluridine (Herpes)
Currently, flaviviruses such as Zika, dengue, and West Nile virus lack specific antiviral treatments. Given their similarities to hepatitis C, for which effective nucleoside analog drugs exist, researchers are investigating nucleoside analogs as potential therapies. The adaptability of these drugs is exemplified by remdesivir, originally developed for Ebola and later repurposed for COVID-19 treatment.2
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Nucleoside Analogs in Cancer Therapy
Nucleoside analogs also play a key role in chemotherapy, improving outcomes for cancer patients. Examples include:
- Cytarabine – Used for acute myeloid leukemia
- Gemcitabine – Used for lung, pancreatic, and recurrent ovarian cancers
However, resistance can limit their effectiveness. Mechanisms such as impaired uptake, reduced activation, or increased degradation by cellular enzymes can impact drug efficacy. Alternative administration methods and combination therapies are being explored to overcome these challenges.
Nucleoside Analogs as Antibacterial Agents
With antibiotic resistance becoming a major public health concern, researchers are exploring nucleoside analogs as potential antibacterial agents.
Some clinically approved drugs, including gemcitabine, zidovudine, and fluorinated pyrimidines (such as trifluridine and idoxuridine), have shown promise in combating resistant bacterial strains. Ongoing studies continue to investigate their efficacy and potential applications.
Challenges: Resistance and Side Effects
Drug Resistance
Despite their effectiveness, nucleoside analogs are not without challenges. Resistance can develop through genetic mutations, particularly in enzymes responsible for phosphorylation. Even a single mutation can render a drug ineffective.
Fortunately, the availability of multiple nucleoside analogs allows for alternative treatment options when resistance arises.
Potential for Liver Damage
One significant concern associated with nucleoside analog therapy is liver toxicity. Hepatic injury can occur through several mechanisms, including:
Mitochondrial toxicity – Some nucleoside analogs disrupt mitochondrial DNA synthesis, leading to severe side effects such as neuropathy, myopathy, bone marrow suppression, pancreatitis, and liver damage. This was observed with fialuridine, which was withdrawn after fatal outcomes in clinical trials.
Lactic acidosis and liver failure – Mitochondrial dysfunction can lead to metabolic complications such as lactic acidosis and microvesicular steatosis.
Acute hypersensitivity and toxicity – Though rare, some nucleoside analogs can produce toxic metabolites or exacerbate pre-existing liver conditions, such as hepatitis B reactivation after treatment withdrawal.3
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Conclusion
Nucleoside analogs have been a cornerstone of antiviral and cancer treatments for decades and are now being explored for antibacterial applications.
While resistance and potential side effects remain concerns, the benefits of these drugs continue to outweigh the risks. Ongoing research aims to enhance their effectiveness and safety, ensuring they remain vital tools in modern medicine.
Resources
- Muggia, F, Diaz, I & Peters, G.J (2012) Nucleoside and nucleobase analogs in cancer treatment: not only sapacitabine, but also gemcitabine \Expert Opinion on Investigational Drugs Issue 4 [Accessed online 11th July 2021] https://www.tandfonline.com/doi/full/10.1517/13543784.2012.666236
- Eyer, L et al. (2018) Nucleoside analogs as a rich source of antiviral agents active against arthropod-borne flaviviruses Antiviral Chemistry Chemotherapy 26 [Accessed online 11th July 2021] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5890575/
- Thomson, J.M & Lamont, I.L. (2019) Nucleoside Analogues as Antibacterial Agents Front Microbiol. 10 page 952 [Accessed online 11th July 2021] https://www.frontiersin.org/articles/10.3389/fmicb.2019.00952/full
Further Reading