Reverse-transcriptase inhibitor

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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.

Contents

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.[ citation needed ]

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.[ citation needed ]

Types

RTIs come in four forms:

The antiviral effect 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. Unfortunately, NRTIs/NtRTIs compete as substrates for not only viral but also host DNA synthesis, acting as chain terminators for both. The former explains NRTIs'/NtRTIs' antiviral effect, while the latter explains their drug toxicity/side effects.[ citation needed ]

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.[ citation needed ]

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. NRTIs can induce mitochondrial impairment that leads to a number of adverse events, including symptomatic lactic acidosis. [2]

Nucleotide analog reverse-transcriptase inhibitors (NtARTIs or NtRTIs)

As described above, host cells phosphorylate nucleoside analogs to nucleotide analogs. The latter serve as poison building blocks (chain terminators) for both viral and host DNA, causing respectively the desired antiviral effect and 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.[ citation needed ]

  • 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:[ citation needed ]

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).[ citation needed ]

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. It is orally available, long acting antiviral, being tested as ART against HIV-1. [5]

Portmanteau inhibitors

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

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). [6] [7] 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. [8] [9] A virus with Q151M alone is intermediately resistant to zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), and slightly resistant to abacavir (ABC). [10] [11] 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). [11] [12]

The second mechanism is the excision or the hydrolytic removal of the incorporated drug or 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 'unblocks' the DNA chain, allowing it to be extended, and replication to continue. [13] 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). [13] [14] [15] Other mutations including insertions and deletions in the background of the above mutations also confer resistance via enhanced excision. [11]

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. [16] 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. [17] 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, [18] [19] 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. [20] [21] 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. [22] [23]

See also

Related Research Articles

The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multiple drugs that act on different viral targets is known as highly active antiretroviral therapy (HAART). HAART decreases the patient's total burden of HIV, maintains function of the immune system, and prevents opportunistic infections that often lead to death. HAART also prevents the transmission of HIV between serodiscordant same-sex and opposite-sex partners so long as the HIV-positive partner maintains an undetectable viral load.

<span class="mw-page-title-main">Zalcitabine</span> Chemical compound

Zalcitabine, also called dideoxycytidine, is a nucleoside analog reverse-transcriptase inhibitor (NRTI) sold under the trade name Hivid. Zalcitabine was the third antiretroviral to be approved by the Food and Drug Administration (FDA) for the treatment of HIV/AIDS. It is used as part of a combination regimen.

<span class="mw-page-title-main">Lamivudine</span> Chemical compound

Lamivudine, commonly called 3TC, is an antiretroviral medication used to prevent and treat HIV/AIDS. It is also used to treat chronic hepatitis B when other options are not possible. It is effective against both HIV-1 and HIV-2. It is typically used in combination with other antiretrovirals such as zidovudine, dolutegravir, and abacavir. Lamivudine may be included as part of post-exposure prevention in those who have been potentially exposed to HIV. Lamivudine is taken by mouth as a liquid or tablet.

<span class="mw-page-title-main">Emtricitabine</span> Antiretroviral drug used to treat HIV infection

Emtricitabine, with trade name Emtriva, is a nucleoside reverse-transcriptase inhibitor (NRTI) for the prevention and treatment of HIV infection in adults and children. In 2019, it was the 494th most commonly prescribed medication in the United States, with more than 3 thousand prescriptions.

<span class="mw-page-title-main">Tenofovir disoproxil</span> Antiviral drug used to treat or prevent HIV and hepatitis infections

Tenofovir disoproxil, sold under the trade name Viread among others, is a medication used to treat chronic hepatitis B and to prevent and treat HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for prevention of HIV/AIDS among those at high risk before exposure, and after a needlestick injury or other potential exposure. It is sold both by itself and together in combinations such as emtricitabine/tenofovir, efavirenz/emtricitabine/tenofovir, and elvitegravir/cobicistat/emtricitabine/tenofovir. It does not cure HIV/AIDS or hepatitis B. It is available by mouth as a tablet or powder.

<span class="mw-page-title-main">Nevirapine</span> Chemical compound

Nevirapine (NVP), sold under the brand name Viramune among others, is a medication used to treat and prevent HIV/AIDS, specifically HIV-1. It is generally recommended for use with other antiretroviral medications. It may be used to prevent mother to child spread during birth but is not recommended following other exposures. It is taken by mouth.

<span class="mw-page-title-main">Entecavir</span> Chemical compound

Entecavir (ETV), sold under the brand name Baraclude, is an antiviral medication used in the treatment of hepatitis B virus (HBV) infection. In those with both HIV/AIDS and HBV antiretroviral medication should also be used. Entecavir is taken by mouth as a tablet or solution.

<span class="mw-page-title-main">Efavirenz</span> Antiretroviral medication

Efavirenz (EFV), sold under the brand names Sustiva among others, is an antiretroviral medication used to treat and prevent HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needlestick injury or other potential exposure. It is sold both by itself and in combination as efavirenz/emtricitabine/tenofovir. It is taken by mouth.

<span class="mw-page-title-main">Nucleoside analogue</span> Biochemical compound

Nucleoside analogues are structural analogues of a nucleoside, which normally contain a nucleobase and a sugar. Nucleotide analogues are analogues of a nucleotide, which normally has one to three phosphates linked to a nucleoside. Both types of compounds can deviate from what they mimick in a number of ways, as changes can be made to any of the constituent parts. They are related to nucleic acid analogues.

<span class="mw-page-title-main">Lamivudine/zidovudine</span> Combination drug for HIV

Lamivudine/zidovudine, sold under the brand name Combivir among others, is a fixed-dose combination antiretroviral medication used to treat HIV/AIDS. It contains two antiretroviral medications, lamivudine and zidovudine. It is used together with other antiretrovirals. It is taken by mouth twice a day.

<span class="mw-page-title-main">Efavirenz/emtricitabine/tenofovir</span> Combination drug for HIV

Efavirenz/emtricitabine/tenofovir, sold under the brand name Atripla among others, is a fixed-dose combination antiretroviral medication used to treat HIV/AIDS. It contains efavirenz, emtricitabine, and tenofovir disoproxil. It can be used by itself or together with other antiretroviral medications. It is taken by mouth.

<span class="mw-page-title-main">Resistance mutation (virology)</span> Virus mutation

A resistance mutation is a mutation in a virus gene that allows the virus to become resistant to treatment with a particular antiviral drug. The term was first used in the management of HIV, the first virus in which genome sequencing was routinely used to look for drug resistance. At the time of infection, a virus will infect and begin to replicate within a preliminary cell. As subsequent cells are infected, random mutations will occur in the viral genome. When these mutations begin to accumulate, antiviral methods will kill the wild type strain, but will not be able to kill one or many mutated forms of the original virus. At this point a resistance mutation has occurred because the new strain of virus is now resistant to the antiviral treatment that would have killed the original virus. Resistance mutations are evident and widely studied in HIV due to its high rate of mutation and prevalence in the general population. Resistance mutation is now studied in bacteriology and parasitology.

<span class="mw-page-title-main">Rilpivirine</span> HIV treatment

Rilpivirine, sold under the brand names Edurant and Rekambys, is a medication, developed by Tibotec, used for the treatment of HIV/AIDS. It is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with higher potency, longer half-life and reduced side-effect profile compared with older NNRTIs such as efavirenz.

<span class="mw-page-title-main">Apricitabine</span> Chemical compound

Apricitabine is an experimental nucleoside reverse transcriptase inhibitor (NRTI) against HIV. It is structurally related to lamivudine and emtricitabine, and, like these, is an analogue of cytidine.

<span class="mw-page-title-main">Stampidine</span> Medication

Stampidine is an experimental nucleoside reverse transcriptase inhibitor (NRTI) with anti-HIV activity.

<span class="mw-page-title-main">Elvucitabine</span> Medication

Elvucitabine is an experimental nucleoside reverse transcriptase inhibitor (NRTI), developed by Achillion Pharmaceuticals, Inc. for the treatment of HIV infection.

Non-nucleoside reverse-transcriptase inhibitors (NNRTIs) are antiretroviral drugs used in the treatment of human immunodeficiency virus (HIV). NNRTIs inhibit reverse transcriptase (RT), an enzyme that controls the replication of the genetic material of HIV. RT is one of the most popular targets in the field of antiretroviral drug development.

Discovery and development of nucleoside and nucleotide reverse-transcriptase inhibitors began in the 1980s when the AIDS epidemic hit Western societies. NRTIs inhibit the reverse transcriptase (RT), an enzyme that controls the replication of the genetic material of the human immunodeficiency virus (HIV). The first NRTI was zidovudine, approved by the U.S. Food and Drug Administration (FDA) in 1987, which was the first step towards treatment of HIV. Six NRTI agents and one NtRTI have followed. The NRTIs and the NtRTI are analogues of endogenous 2´-deoxy-nucleoside and nucleotide. Drug-resistant viruses are an inevitable consequence of prolonged exposure of HIV-1 to anti-HIV drugs.

<span class="mw-page-title-main">Abacavir/dolutegravir/lamivudine</span> Drug combination for HIV

Abacavir/dolutegravir/lamivudine, sold under the brand name Triumeq among others, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. It is a combination of three medications with different and complementary mechanisms of action: abacavir, dolutegravir and lamivudine.

<span class="mw-page-title-main">Bictegravir/emtricitabine/tenofovir alafenamide</span> Fixed dose combination HIV drug

Bictegravir/emtricitabine/tenofovir alafenamide, sold under the brand name Biktarvy, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. One tablet, taken orally once daily, contains 50 mg bictegravir, 200 mg emtricitabine, and 25 mg tenofovir alafenamide. It was approved for use in the United States in February 2018, and for use in the European Union in June 2018.

References

  1. ↑ Islatravir
  2. ↑ Claessens, Yann-Erick; Chiche, Jean-Daniel; Mira, Jean-Paul; Cariou, Alain (2003). "Bench-to-bedside review: Severe lactic acidosis in HIV patients treated with nucleoside analogue reverse transcriptase inhibitors". Critical Care. 7 (3): 226–232. doi: 10.1186/cc2162 . PMC   270672 . PMID   12793872.
  3. ↑ Al-Salama, Zaina T. (October 2017). "Elsulfavirine: First Global Approval". Drugs. 77 (16): 1811–1816. doi:10.1007/s40265-017-0820-3. ISSN   0012-6667. PMID   28940154. S2CID   25316512.
  4. ↑ "Elpida Combi (tenofovir+elsulfavirine+emtricitabine) Film-Coated Tablets. Full Prescribing Information". Russian State Register of Medicines (in Russian).
  5. ↑ Derbalah, Abdallah; Karpick, Hayley Christine; Maize, Holly; Skersick, Preston; Cottrell, Mackenzie; Rao, Gauri G. (2022-07-01). "Role of islatravir in HIV treatment and prevention: an update". Current Opinion in HIV and AIDS. 17 (4): 240–246. doi:10.1097/COH.0000000000000740. ISSN   1746-6318. PMID   35762379. S2CID   250078665.
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  7. ↑ Sarafianos, SG; Das, K; Clark Jr, AD; Ding, J; Boyer, PL; Hughes, SH; Arnold, E (1999). "Lamivudine (3TC) resistance in HIV-1 reverse transcriptase involves steric hindrance with beta-branched amino acids". Proceedings of the National Academy of Sciences of the United States of America. 96 (18): 10027–32. Bibcode:1999PNAS...9610027S. doi: 10.1073/pnas.96.18.10027 . PMC   17836 . PMID   10468556.
  8. ↑ Shafer, RW; Kozal, MJ; Winters, MA; Iversen, AK; Katzenstein, DA; Ragni, MV; Meyer Wa, 3rd; Gupta, P; et al. (1994). "Combination therapy with zidovudine and didanosine selects for drug-resistant human immunodeficiency virus type 1 strains with unique patterns of pol gene mutations". The Journal of Infectious Diseases. 169 (4): 722–9. doi:10.1093/infdis/169.4.722. PMID   8133086.{{cite journal}}: CS1 maint: numeric names: authors list (link)
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  10. ↑ Maeda, Y; Venzon, DJ; Mitsuya, H (1998). "Altered drug sensitivity, fitness, and evolution of human immunodeficiency virus type 1 with pol gene mutations conferring multi-dideoxynucleoside resistance". The Journal of Infectious Diseases. 177 (5): 1207–13. doi:10.1086/515282. PMID   9593005.
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  13. 1 2 Meyer, PR; Matsuura, SE; Mian, AM; So, AG; Scott, WA (1999). "A mechanism of AZT resistance: an increase in nucleotide-dependent primer unblocking by mutant HIV-1 reverse transcriptase". Molecular Cell. 4 (1): 35–43. doi: 10.1016/S1097-2765(00)80185-9 . PMID   10445025.
  14. ↑ Boyer, PL; Sarafianos, SG; Arnold, E; Hughes, SH (2001). "Selective excision of AZTMP by drug-resistant human immunodeficiency virus reverse transcriptase". Journal of Virology. 75 (10): 4832–42. doi:10.1128/JVI.75.10.4832-4842.2001. PMC   114238 . PMID   11312355.
  15. ↑ Arion, D; Kaushik, N; McCormick, S; Borkow, G; Parniak, MA (1998). "Phenotypic mechanism of HIV-1 resistance to 3'-azido-3'-deoxythymidine (AZT): increased polymerization processivity and enhanced sensitivity to pyrophosphate of the mutant viral reverse transcriptase". Biochemistry. 37 (45): 15908–17. doi:10.1021/bi981200e. PMID   9843396.
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  17. ↑ Johnson, VA; Brun-Vezinet, F; Clotet, B; Gunthard, HF; Kuritzkes, DR; Pillay, D; Schapiro, JM; Richman, DD (2009). "Update of the drug resistance mutations in HIV-1: December 2009". Topics in HIV Medicine. 17 (5): 138–45. PMID   20068260.
  18. ↑ Das, Kalyan; Sarafianos, SG; Clark Jr, AD; Boyer, PL; Hughes, SH; Arnold, E (2007). "Crystal structures of clinically relevant Lys103Asn/Tyr181Cys double mutant HIV-1 reverse transcriptase in complexes with ATP and non-nucleoside inhibitor HBY 097". J Mol Biol. 365 (1): 77–89. doi:10.1016/j.jmb.2006.08.097. PMID   17056061.
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  20. ↑ Ren, J; Nichols, C; Bird, L; Chamberlain, P; Weaver, K; Short, S; Stuart, DI; Stammers, DK (2001). "Structural mechanisms of drug resistance for mutations at codons 181 and 188 in HIV-1 reverse transcriptase and the improved resilience of second generation non-nucleoside inhibitors". Journal of Molecular Biology. 312 (4): 795–805. doi:10.1006/jmbi.2001.4988. PMID   11575933.
  21. ↑ Das, K; Ding, J; Hsiou, Y; Clark Jr, AD; Moereels, H; Koymans, L; Andries, K; Pauwels, R; et al. (1996). "Crystal structures of 8-Cl and 9-Cl TIBO complexed with wild-type HIV-1 RT and 8-Cl TIBO complexed with the Tyr181Cys HIV-1 RT drug-resistant mutant". Journal of Molecular Biology. 264 (5): 1085–100. doi:10.1006/jmbi.1996.0698. PMID   9000632.
  22. ↑ Hsiou, Y; Das, K; Ding, J; Clark Jr, AD; Kleim, JP; Rösner, M; Winkler, I; Riess, G; et al. (1998). "Structures of Tyr188Leu mutant and wild-type HIV-1 reverse transcriptase complexed with the non-nucleoside inhibitor HBY 097: inhibitor flexibility is a useful design feature for reducing drug resistance". Journal of Molecular Biology. 284 (2): 313–23. doi:10.1006/jmbi.1998.2171. PMID   9813120.
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