Difference Between Nucleoside and Nucleotide Reverse Transcriptase Inhibitors

The key difference between nucleoside and nucleotide reverse transcriptase inhibitors is that nucleoside reverse transcriptase inhibitors should be phosphorylated by host’s cellular kinases while nucleotide reverse transcriptase inhibitors do not need to undergo initial phosphorylation.

Reverse transcriptase is an enzyme that converts RNA molecule into ssDNA. HIV and retroviruses possess this enzyme to synthesize ssDNA from their RNA genome within the host cell. Thus, it is possible to prevent the infections of HIV and other retroviruses by inhibiting the activity of the reverse transcriptase enzyme, thereby preventing the synthesis of viral genomes and viral multiplication. Reverse transcriptase inhibitors are a class of antiretroviral drugs used to treat this kind of viral infections. These drugs target the reverse transcriptase enzyme and prevent its catalytic action, blocking the synthesis of DNA from viral RNA. Nucleoside and nucleotide reverse transcriptase inhibitors are two types of drugs. These inhibitors are very important, especially in the treatments of AIDS.

CONTENTS

1. Overview and Key Difference
2. What are Nucleoside Reverse Transcriptase Inhibitors
3. What are Nucleotide Reverse Transcriptase Inhibitors
4. Similarities Between Nucleoside and Nucleotide Reverse Transcriptase Inhibitors
5. Side by Side Comparison – Nucleoside vs Nucleotide Reverse Transcriptase Inhibitors in Tabular Form
6. Summary

What are Nucleoside Reverse Transcriptase Inhibitors?

A nucleoside is a nucleotide without a phosphate group. They are the building blocks of nucleic acids: DNA and RNA. Thus, nucleosides are essential components when synthesizing DNA strands. Further, reverse transcriptase adds nucleosides one by one and synthesizes the new DNA strand. Each nucleoside has a 3’hydroxyl group to bind with the next nucleotide via a phosphodiester bond. Nucleoside reverse transcriptase inhibitors are analogues of natural nucleosides. However, they lack the 3’ OH group to form 5′–3′ phosphodiester bond to extend the new strand. Therefore, once they get attached to synthesizing viral DNA chain, the synthesis is terminated and the extending of the new strand is ceased. Thus, the synthesis of viral DNA is interrupted, halting the viral replication and multiplication processes. Ultimately, the viral infection does not spread within the host.

Moreover, nucleoside reverse transcriptase inhibitors should be activated by phosphorylation using the host’s cellular kinases. Once activated, they complete with natural viral nucleotides and bind to the growing strand and terminate the extension of the viral DNA. In fact, nucleoside reverse transcriptase inhibitors are analogues of natural purines and pyrimidines. Zidovudine, didanosine, stavudine, zalcitabine, lamivudine and abacavir are several drugs which are nucleoside reverse transcriptase inhibitors.

What are Nucleotide Reverse Transcriptase Inhibitors?

Nucleotide reverse transcriptase inhibitors are the second type of antiretroviral drugs used in the treatments of HIV and other retroviral infections. They work as competitive substrate inhibitors similar to nucleoside reverse transcriptase inhibitors. Moreover, the principal of working against viruses is also the same with nucleoside reverse transcriptase inhibitors.

However, one major difference is that nucleotide reverse transcriptase inhibitors avoid the initial phosphorylation within the host. But, they require the phosphorylation of phosphonate nucleotide analogues into the phosphonate-diphosphate state for anti-viral activity. Tenofovir and Adefovir are two types of drugs that are nucleotide reverse transcriptase inhibitors.

What are the Similarities Between Nucleoside and Nucleotide Reverse Transcriptase Inhibitors?

• Nucleoside and nucleotide reverse transcriptase inhibitors are two types of drugs important in treating HIV and retroviral infections.
• Both are antiretroviral drugs.
• They are analogues of the naturally occurring deoxynucleotides such as cytidine, guanosine, thymidine and adenosine.
• Their mechanism of action is the same.
• They work as competitive substrate inhibitors.
• Moreover, they work as chain terminators.
• Both types of inhibitors lack the 3’OH group.
• These drugs may result in side effects such as headache, nausea, vomiting, diarrhoea and stomach problems

What is the Difference Between Nucleoside and Nucleotide Reverse Transcriptase Inhibitors?

The key difference between nucleoside and nucleotide reverse transcriptase inhibitors is that the nucleoside reverse transcriptase inhibitors need to undergo three-step phosphorylation to activate antiviral activity, while the nucleotide reverse transcriptase inhibitors do not need to undergo initial phosphorylation step to activate their antiviral activities. Other than this difference, both types of drugs show similarities in the principle of action, side effects, structure, etc.

Summary – Nucleoside vs Nucleotide Reverse Transcriptase Inhibitors

Nucleoside and nucleotide reverse transcriptase inhibitors are two types of antiretroviral drugs that help to treat AIDS and other retroviral infections. They inhibit the catalytic function of the viral reverse transcriptase enzyme by acting as competitive substrate inhibitors. Both cease the synthesis of the growing viral DNA strand. Furthermore, they are analogues of naturally occurring deoxyribonucleotides. But they lack 3’ OH group to form phosphodiester bond with the next nucleotide. The key difference between nucleoside and nucleotide reverse transcriptase inhibitors is the initial phosphorylation to activate the antiviral activity. In that aspect, nucleoside reverse transcriptase should undergo three steps phosphorylation while nucleotide reverse transcriptase inhibitors bypass initial phosphorylation.

Reference:

1. “Reverse-Transcriptase Inhibitor.” Wikipedia, Wikimedia Foundation, 27 July 2019, Available here.
2. “Reverse Transcriptase Inhibitors.” Reverse Transcriptase Inhibitors – an Overview | ScienceDirect Topics, Available here.

Image Courtesy:

1. ” Zidovudine” By Benrr101 – 100% My own work (Public Domain) via Commons Wikimedia
2. “Adefovir” By Fvasconcellos – Own work (Public Domain) via Commons Wikimedia