What is the Difference Between NRTI and NNRTI

The main difference between NRTI and NNRTI is that NRTI is a competitive inhibitor of reverse transcriptase whereas NNRTI is a non-competitive inhibitor of reverse transcriptase.  

NRTI and NNRTI are two types of reverse transcriptase inhibitors (RTI), a class of antiretroviral drugs used in treating HIV and hepatitis B. They inhibit the activity of the enzyme reverse transcriptase.

Key Areas Covered

1. What is NRTI
     – Definition, Features, Function
2. What is NNRTI
     – Definition, Features, Function
3. Similarities Between NRTI and NNRTI
     – Outline of Common Features
4. Difference Between NRTI and NNRTI
     – Comparison of Key Differences

Key Terms

NNRTI, NRTI

What is NRTI

NRTI, or nucleoside analog reverse-transcriptase inhibitor, is a drug with antiviral properties. NRTIs are analogous to naturally occurring deoxynucleotides used in the synthesis of viral DNA. They compete with deoxynucleotides for viral transcription and bind with the viral DNA. The incorporation of NRTI blocks the transcription of viral DNA inside the cell. Although deoxynucleotides contain 3′-hydroxyl group on the deoxyribose moiety, NRTIs do not contain such a part in the molecule. Therefore, with their incorporation into the growing viral DNA strands, no more nucleotides can be added. This process is known as chain termination.

Figure 1: HIV

Furthermore, NRTIs are classical competitive inhibitors that inhibit the action of the enzyme reverse transcriptase by competing with the substrate. However, apart from the viral DNA transcription, NTRIs compete with the host DNA transcription. Therefore, this leads to drug toxicity and side effects. Some examples of NRTIs are Lamivudine (3TC), Emtricitabine (FTC), Tenofovir disoproxil fumarate (TDF), and Tenofovir alafenamide (TAF).

What is NNRTI

NNRTI, or non-nucleoside reverse transcriptase inhibitor, is another type of antiretroviral drug. However, it is a non-competitive inhibitor for the reverse transcriptase enzyme. Therefore, it binds with the reverse transcriptase enzyme directly. This binding inhibits the movement of protein domains of the reverse transcriptase enzyme. It also stops the function of the reverse transcriptase enzyme, stopping the viral DNA transcription. Moreover, the binding of NNTRI into the reverse transcriptase enzyme creates a hydrophobic pocket proximal to the active site of the enzyme. Due to this pocket, a new spatial configuration occurs in the enzyme.

Figure 2: Reverse Transcriptase

The new spatial arrangement of the enzyme is a different one from the regular enzyme conformation. This makes a new configuration at the substrate binding site of the enzyme. This inhibits the binding of substrate to the enzyme. Therefore, the overall DNA synthesis gets slow. However, due to the non-competitive inhibition, NNRTIs are not effective against HIV-2 reverse transcriptase. Examples of NNRTIs are delavirdine (DLV), etravirine (ETR), nevirapine (NVP), doravirine (DOR), and rilpivirine (RPV).

Similarities Between NRTI and NNRTI

• NRTI and NNRTI are two types of retroviral drugs that inhibit the activity of the enzyme reverse transcriptase.
• They are important in treating HIV and hepatitis B.
• They inhibit viral DNA replication.

Difference Between NRTI and NNRTI

Definition

NRTI refers to a class of drugs that inhibit the HIV-1 RT enzyme by competing with natural nucleosides (such as dTTP, dCTP, dGTP, and dATP), while NNRTI refers to small molecule drugs that bind directly to the active site of HIV-1 reverse transcriptase.

Function

NRTI incorporates into the viral DNA and blocks the transcription, while NNRTI binds to the reverse transcriptase and changes the special configuration of the enzyme.

Type of Inhibition

Moreover, NRTI is a competitive inhibitor, while NNRTI is a non-competitive inhibitor.

Examples

Examples of NRTI include Lamivudine (3TC), Emtricitabine (FTC), Tenofovir disoproxil fumarate (TDF), and Tenofovir alafenamide (TAF) while examples of NNRTI include delavirdine (DLV), etravirine (ETR), nevirapine (NVP), doravirine (DOR), and rilpivirine (RPV).

Conclusion

In brief, NRTI and NNRTI are two types of antiretroviral drugs that inhibit the transcription of retroviruses. NRTI is a competitive inhibitor that completes with the nucleosides to bind and block the growing DNA during transcription. Some examples of NRTI include Lamivudine (3TC), Emtricitabine (FTC), Tenofovir disoproxil fumarate (TDF), and Tenofovir alafenamide (TAF). In comparison, NNRTI is a non-competitive inhibitor that binds to the reverse transcriptase enzyme to change the spatial configuration of the enzyme. This also inhibits the transcription of viruses. Examples of NNRTI include delavirdine (DLV), etravirine (ETR), nevirapine (NVP), doravirine (DOR), and rilpivirine (RPV). Therefore, the main difference between NRTI and NNRTI is the type of inhibition of transcription in retroviruses by each type of drug.

References:                     

1. Patel PH, Zulfiqar H. Reverse Transcriptase Inhibitors. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-.

Image Courtesy:

1. “HI-virion-structure en” By Thomas Splettstoesser – Own work (CC-BY SA 4.0) via Commons Wikimedia
2. “Reverse transcriptase 3KLF labels” By Thomas Splettstoesser – Own Work (CC-BY SA 3.0) via Commons Wikimedia