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{{Short description|Class of antiretroviral drug}}
'''Reverse-transcriptase inhibitors''' ('''RTIs''') are a class of [[antiretroviral drug]]s used to treat [[HIV]] infection or
==Mechanism of action==
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.{{cn|date=November 2022}}
A similar process occurs with other types of viruses. The hepatitis B virus, for example, carries its genetic material in the form of DNA, and employs an RNA-dependent DNA polymerase to replicate. Some of the same compounds used as RTIs can also block HBV replication; when used in this way they are referred to as polymerase inhibitors.{{cn|date=November 2022}}
==Types==
RTIs come in
* [[Nucleoside]] analog reverse-transcriptase inhibitors (NARTIs or NRTIs)
* [[Nucleotide]] analog reverse-transcriptase inhibitors (NtARTIs or NtRTIs)
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The [[antiviral drug|antiviral effect]] of NRTIs and NtRTIs is essentially the same; they are analogues of the naturally occurring [[nucleotide|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 inhibitor|competitive substrate inhibitors]].
Unfortunately, NRTIs/NtRTIs compete as substrates for not only viral but also host [[DNA synthesis]], acting as [[chain termination|chain terminators]] for both. The former explains NRTIs'/NtRTIs' [[antiviral drug|antiviral effect]], while the latter explains their [[Adverse effect#Medications|drug toxicity/side effects]].{{cn|date=November 2022}}
In contrast, NNRTIs have a completely different mode of action. NNRTIs block reverse transcriptase by binding directly to the enzyme. NNRTIs are not incorporated into the viral DNA like NRTIs, 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 inhibition|non-competitive inhibitors]] of reverse transcriptase.{{cn|date=November 2022}}
===Nucleoside analog reverse-transcriptase inhibitors (NARTIs or NRTIs){{anchor|Nucleoside analog reverse-transcriptase inhibitor}}<!-- This is a more generic anchor. -->===
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. NRTIs can induce mitochondrial impairment that leads to a number of adverse events, including symptomatic lactic acidosis.<ref name=sidee>{{cite journal | first1=Yann-Erick |last1=Claessens |first2=Jean-Daniel |last2=Chiche |first3=Jean-Paul |last3=Mira |first4=Alain |last4=Cariou| title = Bench-to-bedside review: Severe lactic acidosis in HIV patients treated with nucleoside analogue reverse transcriptase inhibitors| journal = Critical Care| date = 2003 |volume=7 |issue=3 |pages=226–232 |doi=10.1186/cc2162 | pmid = 12793872|pmc=270672 |doi-access=free }}</ref>
* [[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]], also called ddI, with the trade names Videx and Videx EC, was the second FDA-approved antiretroviral drug. It is an analog of adenosine.
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* [[Entecavir]], also called ETV, is a guanosine analog used for hepatitis B under the trade name Baraclude. It is not approved for HIV treatment.
* [[Truvada]], made of emtricitabine and tenofovir disoproxil fumarate, is used to treat and prevent HIV. It is approved for HIV prevention in the US and manufactured by Gilead.
* [[Azvudine]], also called RO-0622. It has been investigated as a possible treatment of [[HIV/AIDS|AIDS]], [[hepatitis C]], and [[SARS-CoV-2]]
====Nucleotide analog reverse-transcriptase inhibitors (NtARTIs or NtRTIs){{anchor|Nucleotide analog reverse-transcriptase inhibitor}}<!-- This is a more generic anchor. -->====
As described above, host cells [[phosphorylation|phosphorylate]] [[nucleoside]] analogs to [[nucleotide]] analogs. The latter serve as poison building blocks ([[chain termination|chain terminators]]) for both viral and host DNA, causing respectively the desired [[antiviral drug|antiviral effect]] and [[Adverse effect#Medications|drug toxicity/side effects]]. Taking [[phosphonate]] [[nucleotide]] analog reverse-transcriptase inhibitors (NtARTIs or NtRTIs) directly obviates the initial [[phosphorylation]] step, but host enzymes must still phosphorylate the phosphonate nucleotide analogue to the phosphonate-diphosphate state for anti-viral activity. These molecules were first synthesized by [[Antonin Holy]] at the [[Czech Academy of Sciences]], and commercialized by [[Gilead Sciences|Gilead]].{{cn|date=November 2022}}
* [[Tenofovir]], also known as TDF is a so-called 'prodrug' with the active compound deactivated by a molecular side chain that dissolves in the human body allowing a low dose of tenofovir to reach the site of desired activity. One example of the prodrug form is tenofovir disoproxil fumarate with the trade name Viread (Gilead Sciences Inc USA). It is approved in the US for the treatment of both HIV and hepatitis B.
* [[Adefovir]], also known as ADV or bis-POM PMPA, has trade names Preveon and [[Hepsera]]. It is not approved by the FDA for treatment of HIV due to toxicity issues, but a lower dose is approved for the treatment of hepatitis B.
While often listed in chronological order, NRTIs/NtRTIs are nucleoside/nucleotide analogues of cytidine, guanosine, thymidine and adenosine:{{cn|date=November 2022}}
* Thymidine analogues: [[zidovudine]] (AZT) and [[stavudine]] (d4T)
* Cytidine analogues: [[zalcitabine]] (ddC), [[lamivudine]] (3TC), and [[emtricitabine]] (FTC)
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===Non-nucleoside reverse-transcriptase inhibitors (NNRTIs){{anchor|Non-nucleoside reverse-transcriptase inhibitor}}<!-- This is a more generic anchor. -->===
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]]).{{cn|date=November 2022}}
* [[Efavirenz]] has the trade names Sustiva and Stocrin.
* [[
* [[
* [[
* [[
* [[Doravirine]]
▲*[[Rilpivirine]] has the trade name Edurant, and was approved by the FDA in May 2011.
* [[Elsulfavirine]], sold as Elpida, was approved by Russian [[Ministry of Health (Russia)|Ministry of Health]] in 2017<ref>{{Cite journal |last=Al-Salama |first=Zaina T. |date=October 2017 |title=Elsulfavirine: First Global Approval |url=https://link.springer.com/10.1007/s40265-017-0820-3 |journal=Drugs |language=en |volume=77 |issue=16 |pages=1811–1816 |doi=10.1007/s40265-017-0820-3 |pmid=28940154 |s2cid=25316512 |issn=0012-6667}}</ref> and is currently used on its own or in fixed-dose combination with tenofovir disoproxil and emtricitabine (Elpida Combi).<ref>{{Cite web |title=Elpida Combi (tenofovir+elsulfavirine+emtricitabine) Film-Coated Tablets. Full Prescribing Information. |url=https://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=272b51b6-d5df-46e6-90f0-ec9089d353e9 |website=Russian State Register of Medicines |language=RU}}</ref>
▲*[[Doravirine]] (MK-1439), also called Pifeltro, is a [[non-nucleoside reverse transcriptase inhibitor]] developed by [[Merck & Co.]] for use in the treatment of [[HIV/AIDS]]. In August 2018, the FDA approved doravirine'''.''' It is also used in a combination tablet as [[doravirine/lamivudine/tenofovir disoproxil fumarate]] (Delstrigo).
===Nucleoside reverse transcriptase translocation inhibitor (NRTTIs)===
This is a new class of antivirals, MK-8591 or [[Islatravir]] being the first agent of this group. Islatravir was developed by [[Merck & Co.]]
===Portmanteau inhibitors===
Researchers have designed molecules which dually inhibit both reverse transcriptase (RT) and integrase (IN). These drugs are a type of "[[portmanteau inhibitor]]s".{{cn|date=November 2022}}
==Mechanisms of
While NRTIs and NNRTIs alike are effective at terminating DNA synthesis and HIV replication, HIV can and eventually does develop mechanisms that confer the virus resistance to the drugs. HIV-1 RT does not have proof-reading activity. This, combined with selective pressure from the drug, leads to mutations in reverse transcriptase that make the virus less susceptible to NRTIs and NNRTIs.
Aspartate residues 110, 185, and 186 in the reverse transcriptase polymerase domain are important in the binding and incorporation of nucleotides. The side chains of residues K65, R72, and Q151 interact with the next incoming nucleotide. Also important is L74, which interacts with the template strand to position it for base pairing with the nucleotide. Mutation of these key amino acids results in reduced incorporation of the analogs.
===NRTI resistance===
There are two major mechanisms of NRTI resistance. The first being reduced incorporation of the nucleotide analog into DNA over the normal nucleotide. This results from mutations in the N-terminal polymerase domain of the reverse transcriptase that reduce the enzyme's affinity or ability to bind to the drug . A prime example for this mechanism is the M184V mutation that confers resistance to lamivudine (3TC) and emtricitabine (FTC).<ref>{{cite journal |last1 = Hachiya | first1 = A | last2 = Kodama | first2 = EN | last3 = Schuckmann | first3 = MM | last4 = Kirby | first4 = KA | last5 = Michailidis | first5 = E | last6 = Sakagami | first6 = Y | last7 = Oka | first7 = S | last8 = Singh | first8 = K | last9 = Sarafianos | first9 = SG | editor1-last = Ambrose | editor1-first = Zandrea |title=K70Q adds high-level tenofovir resistance to "Q151M complex" HIV reverse transcriptase through the enhanced discrimination mechanism |journal=PLOS ONE |volume=6 |issue=1 |pages=e16242 |year=2011 |pmid=21249155 |pmc=3020970 |doi=10.1371/journal.pone.0016242
The second mechanism is the excision or the hydrolytic removal of the incorporated drug or [[pyrophosphate|pyrophosphorolysis]]. This is a reverse of the polymerase reaction in which the pyrophosphate/PPI released during nucleotide incorporation reacts with the incorporated drug (monophosphate) resulting in the release of the triphosphate drug. This
===NNRTI resistance===
NNRTIs do not bind to the active site of the polymerase but in a less conserved pocket near the active site in the p66 subdomain. Their binding results in a conformational change in the reverse transcriptase that distorts the positioning of the residues that bind DNA, inhibiting polymerization.<ref>{{cite journal | last1 = De Clercq | first1 = E | title = The role of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection | journal = Antiviral Research | volume = 38 | issue = 3 | pages = 153–79 | year = 1998 | pmid = 9754886 | doi = 10.1016/S0166-3542(98)00025-4 }}</ref> Mutations in response to NNRTIs decrease the binding of the drug to this pocket. Treatment with a regimen including efavirenz (EFV) and nevirapine (NVP) typically results in mutations L100I, Y181C/I, K103N, V106A/M, V108I, Y188C/H/L and G190A/S.<ref>{{cite journal | last1 = Johnson | first1 = VA | last2 = Brun-Vezinet | first2 = F | last3 = Clotet | first3 = B | last4 = Gunthard | first4 = HF | last5 = Kuritzkes | first5 = DR|author5-link=Daniel Kuritzkes | last6 = Pillay | first6 = D | last7 = Schapiro | first7 = JM | last8 = Richman | first8 = DD | title = Update of the drug resistance mutations in HIV-1: December 2009 | journal = Topics in HIV Medicine | volume = 17 | issue = 5 | pages = 138–45 | year = 2009 | pmid = 20068260 }}</ref>
There are three main mechanisms of NNRTI resistance. In the first NRTI mutations disrupt specific contacts between the inhibitor and the NNRTI binding pocket. An example of this is K103N and K101E which sit at the entrance of the pocket,<ref>{{cite journal | doi = 10.1016/j.jmb.2006.08.097 | last1 = Das | first1 = Kalyan| year = 2007 | last2 = Sarafianos | first2 = SG | last3 = Clark Jr | first3 = AD | last4 = Boyer | first4 = PL | last5 = Hughes | first5 = SH | last6 = Arnold | first6 = E | title = Crystal structures of clinically relevant Lys103Asn/Tyr181Cys double mutant HIV-1 reverse transcriptase in complexes with ATP and non-nucleoside inhibitor HBY 097
==See also==
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{{DNA antivirals}}
{{Enzyme inhibition}}
{{Authority control}}
{{DEFAULTSORT:Reverse-Transcriptase Inhibitor}}
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