Reverse transcriptase inhibitor

Reverse transcriptase inhibitors (RTIs) are a class of antiretroviral drug used to treat HIV infection, tumors^[1], and cancer^[2]. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase enzyme that retroviruses need to reproduce.

Mechanism

When HIV infects a cell, reverse transcriptase copies the viral single stranded RNA genome into a double-stranded viral DNA. The viral DNA is then integrated into the host chromosomal DNA, which then allows host cellular processes, such as transcription and translation to reproduce the virus. RTIs block reverse transcriptase's enzymatic function and prevent completion of synthesis of the double-stranded viral DNA, thus preventing HIV from multiplying.

Types

RTIs come in three forms:

• Nucleoside analog reverse transcriptase inhibitors (NARTIs or NRTIs)
• Nucleotide analog reverse transcriptase inhibitors (NtARTIs or NtRTIs)
• Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

The mode of action of NRTIs and NtRTIs is essentially the same; they are analogues of the naturally occurring deoxynucleotides needed to synthesize the viral DNA and they compete with the natural deoxynucleotides for incorporation into the growing viral DNA chain. However, unlike the natural deoxynucleotides substrates, NRTIs and NtRTIs lack a 3'-hydroxyl group on the deoxyribose moiety. As a result, following incorporation of an NRTI or an NtRTI, the next incoming deoxynucleotide cannot form the next 5'-3' phosphodiester bond needed to extend the DNA chain. Thus, when an NRTI or NtRTI is incorporated, viral DNA synthesis is halted, a process known as chain termination. All NRTIs and NtRTIs are classified as competitive substrate inhibitors.

In contrast, NNRTIs have a completely different mode of action. NNRTIs block reverse transcriptase by binding at a different site on the enzyme, compared to NRTIs and NtRTIs. NNRTIs are not incorporated into the viral DNA but instead inhibit the movement of protein domains of reverse transcriptase that are needed to carry out the process of DNA synthesis. NNRTIs are therefore classified as non-competitive inhibitors of reverse transcriptase.

Nucleoside analog reverse transcriptase inhibitors (NARTIs or NRTIs)

Nucleoside analog reverse transcriptase inhibitors (NARTIs or NRTIs) compose the first class of antiretroviral drugs developed. In order to be incorporated into the viral DNA, NRTIs must be activated in the cell by the addition of three phosphate groups to their deoxyribose moiety, to form NRTI triphosphates. This phosphorylation step is carried out by cellular kinase enzymes.

Zidovudine 

Zidovudine, also called AZT, ZDV, and azidothymidine, has the trade name Retrovir. Zidovudine was the first antiretroviral drug approved by the FDA for the treatment of HIV.

Didanosine 

Didanosine, also called ddI, with the trade names Videx and Videx EC, was the second FDA-approved antiretroviral drug.

Zalcitabine 

Zalcitabine, also called ddC and dideoxycytidine, has the trade name Hivid. This drug has been discontinued by the manufacturer.

Stavudine 

Stavudine, also called d4T, has trade names Zerit and Zerit XR.

Lamivudine 

Lamivudine, also called 3TC, has the trade name Epivir.

Abacavir 

Abacavir, also called ABC, has the trade name Ziagen, is an analog of guanosine.

Emtricitabine 

Emtricitabine, also called FTC, has the trade name Emtriva (formerly Coviracil).

Apricitabine 

Apricitabine, also called ATC. As of 2009, this drug is undergoing Phase-III evaluation, and if successful may achieve FDA approval in 2011.

Nucleotide analog reverse transcriptase inhibitors (NtARTIs or NtRTIs)

Normally, nucleoside analogs are converted into nucleotide analogs by the body. Taking nucleotide analog reverse transcriptase inhibitors (NtARTIs or NtRTIs) directly allows conversion steps to be skipped.

Tenofovir 

Tenofovir, also known as tenofovir disoproxil fumarate, has the trade name Viread.

Adefovir 

Adefovir, also known as bis-POM PMPA, has trade names Preveon and Hepsera. It is not approved by the FDA for treatment of HIV.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are the third class of antiretroviral drugs that were developed. In all cases, patents remain in force until beyond 2007. This class of drugs was first described at the Rega Institute for Medical Research (Belgium)

Efavirenz 

Efavirenz has the trade names Sustiva and Stocrin.

Nevirapine 

Nevirapine has the trade name Viramune.

Delavirdine 

Delavirdine, currently rarely used, has the trade name Rescriptor.

Etravirine 

Etravirine has the trade name Intelence, and was approved by the FDA in 2008.

Portmanteau inhibitors

Researchers have designed molecules which dually inhibit both reverse transcriptase (RT) and integrase (IN). These drugs are a type of "portmanteau inhibitors".

See also

• Discovery and Development of Non-Nucleoside Reverse Transcriptase Inhibitors

References

1. ^ Reverse Transcriptase Inhibitors Down-Regulate Cell Proliferation in Vitro and in Vivo and Restore Thyrotropin Signaling and Iodine Uptake in Human Thyroid Anaplastic Carcinom...
2. ^ Reverse transcriptase inhibitors induce an androgen-dependent phenotype in undifferentiated androgen-independent prostate carcinoma cells. - ASCO

External links

• MeSH Reverse+Transcriptase+Inhibitors