1. Introduction

2. Nucleoside Reverse Transcriptase Inhibitors

3. Non Nucleoside Reverse Transcriptase Inhibitors

4. NNRTIs Resistance

5. NNRTIs Future

6. References

7. External links

Introduction

For viral replication viruses need the reverse transcriptase for the retrotrancription of RNA to DNA during the first phase of replication.

From this point reverse transcriptase inhibitors were evolved, specifically for human immune deficiency virus type 1 (HIV-1).

There are two types of reverse transcriptase inhibitors; nucleoside, and non nucleoside inhibitors.^[1]

Nucleoside Reverse Transcriptase Inhibitors

Nucleoside reverse transcriptase inhibitors (NRTIs) are the first type developed, which are analogous of the purines and pyrimidines involved in the DNA of the virus.

They act by two mechanisms of action: chain terminates, and by competitive binding to functionally essential sites of the reverse transcriptase.^[2]

The following are FDA approved NRTIs for HIV-1: AZT-zidovudine, 3CT-lamivudine, FTC-emtricitabine, ABC-abacavir, and ddI-didanosine.^[3]

Non Nucleoside Reverse Transcriptase Inhibitors

Non nucleoside reverse transcriptase inhibitors (NNRTIs) are non competitive inhibitors ^[3], act by binding to allosteric site of the enzyme, which causes conformational change leading to disruption of the catalytic site and blocking DNA polymerase activity. ^[1]

NNRTIs approved by the FDA for HIV-1 include: first generation nevirapine and delavindine, efavirenz a second generation, and etravirine a third generation. ^[3]

NNRTIs are an important part of the combination called highly active antiretroviral therapy (HAART), which is based on combination of 3 or more anti-HIV drugs to reduce viral resistance.

Advantages of  NNRTIs over NRTIs include lower toxicity, higher potency, higher selectivity, and specificity.

After the use of HAART, mortality rate with AIDS reduced significantly, but we still need the development of new drugs due to viral resistance.^[4]

NNRTIs Resistance

Resistance to NNRTIs emerge from the mutation in the non nucleoside inhibitory binding pocket (NNIBP), by changing in the amino acids in the pocket, which leads to ineffective binding and allowing DNA polymerization to be continued.

Mutations occur as following: change or loss of the hydrophobic interaction, steric hindrance affecting NNIBP's central region, or amino acids substitution.

Resistance to NNRTIs increases with using them in sub-optimal regimen, or with low adherence.

Second generation NNRTIs have lower resistance than first generation, because they adopt different conformational modes within NNIBP, by having flexibility and re-positioning. ^[4]

NNRTIs Future

Newly Rilpivirine (approved in 2011) and dolutergravir (integrase inhibitor) together are approved to be given as single pill, once daily for maintenance therapy of suppressed infection with HIV-1.

To prevent mother to child transmission nevirapine has been used.

Phase 2 trial on Rilpivirine has been completed to use it as long acting formulation for pre-exposure prophylaxis safely.

Pipeline and doravirine are in phase 3 trial to be developed for treatment of HIV-1 infection.

Urea PETT derivative MTV-150 is in it's phase 1 study.

Potent new class (studied in vitro and in a humanized mouse model) for HIV-1 infection is catechol di-ether based NNRTI, and compound 1 (lead compound) showed synergetic effect with other classes of antiviral drugs.^[5]

There is a lot of studies search and discover new lead compounds that cab modified and tailored into novel anti Reverse transcriptase inhibitor with a potential effect against HIV or any other RNA viral infection.^[1][6][7][8]

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References

External links

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