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07-SEPTEMBER-2008 03:17:44 - Reverse transcriptase inhibitor Reverse transcriptase inhibitors RTIs are a class of antiretroviral drug used to treat HIV infection, tumors1, and cancer2. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase enzyme that HIV needs to reproduce. Contents 1 Mechanism 2 Types 2.1 Nucleoside analog reverse transcriptase inhibitors NARTIs or NRTIs 2.2 Nucleotide analog reverse transcriptase inhibitors NtARTIs or NtRTIs 2.3 Non-nucleoside reverse transcriptase inhibitors NNRTIs 2.4 Portmanteau inhibitors 3 References 4 External links 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. 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, causing less toxicity. 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. References ^ Reverse Transcriptase Inhibitors Down-Regulate Cell Proliferation in Vitro and in Vivo and Restore Thyrotropin Signaling and Iodine Uptake in Human Thyroid Anaplastic Carcinom... ^ Reverse transcriptase inhibitors induce an androgen-dependent phenotype in undifferentiated androgen-independent prostate carcinoma cells. - ASCO External links MeSH Reverse+Transcriptase+Inhibitors v d e Antivirals used against HIV HAART primarily J05 Nucleoside Nucleotide Reverse Transcriptase Inhibitors NRTI Abacavir ABC° Dexelvucitabine§ Emtricitabine° Lamivudine 3TC° Tenofovir° Didanosine Zidovudine AZT Apricitabine† Stampidine† Elvucitabine† Racivir† Amdoxovir† Stavudine‡ Zalcitabine‡ Non-Nucleoside Reverse Transcriptase Inhibitors NNRTI Ateviridine§ Capravirine§ Efavirenz° Emivirine§ Lodenosine§ Nevirapine Etravirine Rilpivirine† Loviride‡ Delavirdine‡ Quinotaline§ Protease Inhibitors PI Atazanavir° Brecanavir§ Fosamprenavir° Lopinavir° Darunavir Nelfinavir Ritonavir Saquinavir Tipranavir Amprenavir‡ Indinavir‡ Entry/fusion inhibitors Aplaviroc§ Enfuvirtide Maraviroc Vicriviroc† PRO 140† Ibalizumab† Integrase inhibitors Raltegravir Elvitegravir† Maturation inhibitors Bevirimat† Vivecon† Combined formulations Combivir Atripla Trizivir Truvada Kaletra Epzicom Other experimental agents Foscarnet Hydroxyurea Synergistic enhancers Epigallocatechin gallate Portmanteau inhibitors Globoidnan A Griffithsin Diarylpyrimidines Calanolide A Cyanovirin-N Miltefosine R-roscovitine† °DHHS preferred first-line agent. †Undergoing clinical trials, not FDA approved. ‡Formerly or rarely used agent. §Development terminated. v d e Pharmacology: enzyme inhibition Class Competitive inhibition - Uncompetitive inhibition - Non-competitive inhibition - Suicide inhibition - Mixed inhibition Substrate Oxidoreductase EC 1: Aromatase inhibitors - Lipoxygenase inhibitor - Monoamine oxidase inhibitors - COX-2 inhibitor Transferase EC 2: Integrase inhibitor - Protein kinase inhibitors - Reverse transcriptase inhibitors - COMT inhibitors Hydrolase EC 3: Acetylcholinesterase inhibitors - Phosphodiesterase inhibitors - Protease inhibitors ACE inhibitor, Trypsin inhibitor - Histone deacetylase inhibitor Lyase EC 4: Carbonic anhydrase inhibitors Retrieved from http://en..org/wiki/Reverse_transcriptase_inhibitor Categories: Inhibitors | Antiretroviral drugs Views Article Discussion this page History Personal tools Log in / create account Navigation Main page Contents Featured content Current events Random article Search Go Search Interaction Community portal Recent changes Contact Donate to Help Toolbox What links here Related changes Upload file Special pages Printable version Permanent link Cite this page Languages Bahasa Indonesia 中文 This page was last modified on 9 August 2008, at 19:21
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