reverse transcriptase inhibitor

• 逆転写酵素阻害薬、逆転写酵素阻害剤

WordNet

1. of the transmission gear causing backward movement in a motor vehicle; "in reverse gear"
2. a relation of direct opposition; "we thought Sue was older than Bill but just the reverse was true" (同)contrary, opposite
3. the gears by which the motion of a machine can be reversed (同)reverse gear
4. the side of a coin or medal that does not bear the principal design (同)verso
5. (American football) a running play in which a back running in one direction hands the ball to a back running in the opposite direction
6. an unfortunate happening that hinders or impedes; something that is thwarting or frustrating (同)reversal, setback, blow, black_eye
7. limit, block, or decrease the action or function of; "inhibit the action of the enzyme"; "inhibit the rate of a chemical reaction"
8. control and refrain from showing; of emotions, desires, impulses, or behavior (同)bottle up, suppress
9. limit the range or extent of; "Contact between the young was inhibited by strict social customs"
10. a substance that retards or stops an activity
11. a lapel on a womans garment; turned back to show the reverse side (同)revere
12. turned inside out and resewn; "the reversed collar looked as good as new"

PrepTutorEJDIC

1. (位置・方向・順序などにおいて)『逆の』;裏側の』 / 逆に動かす(動く),バックの / 〈U〉《the reverse》(…の)『反対』,『逆』《+『of』+『名』(『wh』‐節)》》 / 〈U〉《the reverse》(貨幣・メダルなどの)『裏側』,(一般に)(…の)裏面《+『of』+『名』》 / 〈C〉(運命などの)逆転,不運 / 〈U〉後退[装置],逆転[装置] / …‘を'『逆にする』,反対にする;…‘を'裏返す / 〈機械など〉‘を'逆転させる,逆方向に動かす / 〈判決など〉‘を'取り消す,破棄する / (ダンスで)逆に回る / 〈機械などが〉逆方向に動く
2. 〈感情・欲望・行動・作用など〉‘を'抑制する / (…しないように)〈人〉‘を'抑制する,妨げる《+『名』+『from』+『名』(do『ing』)》
3. 抑制する人(物) / 化学反応抑制剤
4. （フランス語）(えりの)裏出し,折り返し
5. 逆にした,反対の,裏返のし;取り消された

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/02/19 09:27:43」(JST)

wiki en

[Wiki en表示]

Reverse-transcriptase inhibitors (RTIs) are a class of antiretroviral drugs used to treat HIV infection or AIDS, and in some cases hepatitis B. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase that is required for replication of HIV and other retroviruses.

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.

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 a 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.

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 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 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, 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.
• Zalcitabine, also called ddC and dideoxycytidine, has the trade name Hivid. This drug has been discontinued by the manufacturer.
• Stavudine, also called d4T, has trade names Zerit and Zerit XR.
• Lamivudine, also called 3TC, has the trade name Zeffix and Epivir. It is approved for the treatment of both HIV and hepatitis B.
• Abacavir, also called ABC, has the trade name Ziagen, is an analog of guanosine.
• Emtricitabine, also called FTC, has the trade name Emtriva (formerly Coviracil). Structurally similar to lamivudine, it is approved for the treatment of HIV and undergoing clinical trials for hepatitis B.
• Entecavir, also called ETV, is a guanosine analog used for hepatitis B under the trade name Baraclude. It is not approved for HIV treatment.
• 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, 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 USA for the treatment of both HIV and hepatitis B.
• Adefovir, also known as bis-POM PMPA, has trade names Preveon and Hepsera. It was 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.

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.

Rilpivirine 

Rilpivirine has the trade name Edurant, and was approved by the FDA in May 2011.

Portmanteau inhibitors

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

Mechanisms of resistance to reverse transcriptase inhibitors

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). Another well characterized set of mutations is the Q151M complex found in multi-drug resistant HIV which decreases reverse transcriptase’s efficiency at incorporating NRTIs, but does not affect natural nucleotide incorporation. The complex includes Q151M mutation along with A62V, V75I, F77L, and F116Y. A virus with Q151M alone is intermediately resistant to zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), and slightly resistant to abacavir (ABC). A virus with Q151M complexed with the other four mutations becomes highly resistant to the above drugs, and is additionally resistant to lamivudine (3TC) and emtricitabine (FTC).

The second mechanism is the excision or the hydrolytic removal of the incorporated drug or pyrophosphorlysis. 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 ‘unblocks’ the DNA chain, allowing it to be extended, and replication to continue. Excision enhancement mutations, typically M41L, D67N, K70R, L210W, T215Y/F, and K219E/Q, are selected for by thymidine analogs AZT and D4T; and are therefore called thymidine analog mutations (TAMs). Other mutations including insertions and deletions in the background of the above mutations also confer resistance via enhanced excision.

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. 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. 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, blocking the entrance/binding of the drug. A second mechanism is the disruption of important interactions on the inside of the pocket. For example Y181C and Y188L result in the loss of important aromatic rings involved in NNRTI binding. The third type of mutations result in changes in the overall conformation or the size of the NNRTI binding pocket. An example is G190E, which creates a steric bulk in the pocket, leaving little or no room for an NNRTI to tightly bind.

See also

• Discovery and development of non-nucleoside reverse-transcriptase inhibitors
• Protease inhibitors
• Discovery and development of nucleoside and nucleotide reverse-transcriptase inhibitors

References

External links

• Reverse Transcriptase Inhibitors at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

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English Journal

•  Tenofovir-induced Fanconi syndrome in a patient with chronic hepatitis B monoinfection.

• Conti F1, Vitale G1, Cursaro C1, Bernardi M1, Andreone P1.
• Annals of hepatology.Ann Hepatol.2016 Mar-Apr;15(2):273-6. doi: 10.5604/16652681.1193725.
•  Tenofovir disoproxil fumarate (TDF) is a nucleotide reverse transcriptase inhibitor indicated for treatment of patients with chronic hepatitis B virus (CHB) and human immunodeficiency virus (HIV) infections. Despite the good safety profile of the drug, Fanconi syndrome is a possible adverse reacti
• PMID 26845606

• Prevalence of drug resistance mutations in HAART patients infected with HIV-1 CRF06_cpx in Estonia.

• Avi R1, Pauskar M1, Karki T1, Kallas E1, Jõgeda EL1, Margus T2, Huik K1, Lutsar I1.
• Journal of medical virology.J Med Virol.2016 Mar;88(3):448-54. doi: 10.1002/jmv.24361. Epub 2015 Sep 21.
• HIV-1 drug resistance mutations (DRMs) and substitutions were assessed after the failure of the first line non-nucleoside reverse transcriptase inhibitors (NNRTIs) + 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) treatment regimens (efavirenz [EFV] + lamivudine[3TC] +�
• PMID 26291050

• Discovery of the Aryl-phospho-indole IDX899, a Highly Potent Anti-HIV Non-nucleoside Reverse Transcriptase Inhibitor.

• Dousson C1, Alexandre FR1, Amador A1, Bonaric S1, Bot S1, Caillet C1, Convard T1, da Costa D1, Lioure MP1, Roland A1, Rosinovsky E1, Maldonado S1, Parsy C1, Trochet C1, Storer R1, Stewart A2, Wang J2, Mayes BA2, Musiu C2, Poddesu B2, Vargiu L2, Liuzzi M2, Moussa A2, Jakubik J2, Hubbard L2, Seifer M2, Standring D2.
• Journal of medicinal chemistry.J Med Chem.2016 Feb 3. [Epub ahead of print]
• Here, we describe the design, synthesis, biological evaluation, and identification of a clinical candidate non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a novel aryl-phospho-indole (APhI) scaffold. NNRTIs are recommended components of highly active antiretroviral therapy (HAART) for
• PMID 26804933

Japanese Journal

• Raltegravir and abacavir/lamivudine in Japanese treatment-naïve and treatment-experienced HIV-infected patients: a 48-week retrospective pilot analysis

• Suzuki Akihito,Uehara Yuki,Saita Mizue,Inui Akihiro,Isonuma Hiroshi,Naito Toshio
• Japanese Journal of Infectious Diseases advpub(0), 2015
• … Abacavir/lamivudine (ABC/3TC) is a nucleoside reverse transcriptase inhibitor used for treating human immunodeficiency virus (HIV). … Raltegravir (RAL) is an integrase strand transfer inhibitor, also recently used for treating HIV because of few side effects. …
• NAID 130005069404

• Safety analysis of Ziagen® (abacavir sulfate) in postmarketing surveillance in Japan

• Kurita Tomoko,Kitaichi Tomomi,Nagao Takako,Miura Toshiyuki,Kitazono Yoshifumi
• Pharmacoepidemiology and Drug Safety 23(4), 361-371, 2014-04
• … Purpose: Abacavir is a nucleoside reverse transcriptase inhibitor indicated for human immunodeficiency virus (HIV) infection. …
• NAID 120005438939

• R-CHOP療法後早期に発症したt(11;17)(q23;p13)/MLL-GAS7転座急性単球性白血病の1例

• 飯岡 大,赤坂 尚司,福塚 勝弘,奥村 敦子,大野 仁嗣
• 天理医学紀要 17(2), 72-80, 2014
• 症例: 66歳女性．びまん性大細胞型B細胞リンパ腫（stage Ⅲ）に対してR-CHOP療法（リツキシマブ, シクロホスファミド, ドキソルビシン, ビンクリスチン, プレドニゾロン）を実施した．原疾患は速やかに寛解に至ったが，5サイクル実施以降，貧血と血小板減少が遷延した．骨髄は低形成で輸血依存状態が続き，さらにR-CHOP療法開始から10.5か月後に顕著な単球増多を認めた． 検査結果: ヘモグ …
• NAID 130004940441

Related Links

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• Reverse transcriptase inhibitor : definition of Reverse ...

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 ...

Related Pictures

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★リンクテーブル★

リンク元	「逆転写酵素阻害薬」
拡張検索	「nonnucleoside reverse transcriptase inhibitor」「nonnucleoside reverse transcriptase inhibitors」
関連記事	「reverse」「inhibit」「inhibitor」「transcriptase」

「逆転写酵素阻害薬」

　　[★]

英

reverse transcriptase inhibitor

関

ddI

• 核酸系逆転写酵素阻害薬
• 非核酸系逆転写酵素阻害薬

「nonnucleoside reverse transcriptase inhibitor」

　　[★] 非ヌクレオシド系逆転写酵素阻害薬 NNRTI

「nonnucleoside reverse transcriptase inhibitors」

　　[★] 非核酸系逆転写酵素阻害薬

「reverse」

　　[★]

• v.

• 逆転させる、逆行する、逆戻りさせる、リバースする

• adj.

• 逆の、逆性の

関

adversely、backward、converse、conversely、inverse、inversely、opposite、oppositely、retro、reversal

　 　 　 　 　 　 　

「inhibit」

　　[★]

• v.

• 抑制する、阻害する、阻止する

関

abrogate、block、depress、depression、deter、inhibition、interdict、prevent、prevention、repress、repression、restrain、restraint、suppress、suppression

　 　 　 　

「inhibitor」

　　[★]

• n.

• 阻害剤、阻害薬、抑制薬、抑制剤、(内在性物質について)インヒビター、抑制物質

関

blocker、depressant、suppressant

　 　

「transcriptase」

　　[★]

• 転写酵素

関

DNA-dependent RNA polymerase、DNA-directed RNA polymerase、RNA polymerase