Integrase inhibitor

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Integrase inhibitors (integration inhibitors) are drugs that have a virustatic effect . These are drugs that inhibit the key enzyme integrase in retroviruses such as HIV . The principle of strand transfer inhibition was first discovered in 2000. The first clinical studies began in 2005, after the development was slowed down until 2000 by a lack of suitable test methods and the high toxicity of some active ingredients. The tolerance seems to be good over a few weeks, but nothing is known about long-term toxicities. The same applies to the development of resistance. Cross-resistance across classes appears to be possible according to initial laboratory data.

effect

In addition to reverse transcriptase and protease, integrase is one of the three key enzymes in the replication cycle of HIV . The integrase consists of 288 amino acids and is encoded by the HIV pol gene. It is involved in the integration of viral DNA into the host DNA in the cell nucleus and is essential for the multiplication of HIV.

The integration of viral DNA takes at least four steps. Each of these steps could theoretically be inhibited. As with entry inhibitors , a distinction may therefore be made between different groups of active ingredients in the future.

Pyranodipyrimidines

Binding of the integrase enzyme in the cytoplasm to the viral DNA: a stable so-called pre-integration complex is created. Pyranodipyrimidines, as integrase DNA binding inhibitors, could inhibit this step.

Processing inhibitors

In a first catalytic step, the integrase separates out a dinucleotide at both ends of the viral DNA and now produces new 3'-hydroxy ends within the pre-integration complex. Possible processing inhibitors are styrylquinolones or diketo acids.

Strand transfer inhibitors (STIs)

After the complex modified in this way has been introduced into the cell nucleus through nuclear pores , the integrase binds to the host DNA. It ensures the docking and irreversible binding of the viral DNA to the host DNA. This step is inhibited by the currently approved integrase inhibitors raltegravir , elvitegravir and dolutegravir .

Gap Repair Inhibitors

The combination of viral DNA and host cell DNA is a product with gaps that is repaired by the host cell's own repair enzymes. The repair can be inhibited, for example, by methylxanthine.

Side effects

The most common (> 10%) adverse events during clinical trials with currently known drugs were diarrhea , nausea, headache and fever. The rate of discontinuation due to adverse events in raltegravir-treated patients was 2 percent compared to 1.4 percent for placebo. Experience from long-term treatment is not yet available.

application areas

They are used to fight the replication of a virus.

Active ingredients

swell

  1. ↑ Hazuda 2000
  2. ^ Nair 2002
  3. ↑ Reviews: Pommier 2005, Lataillade 2006

literature

  • Grinsztejn B, Nguyen BY, Katlama C, et al. Potent antiretroviral effect of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. Abstract 159LB, 13th CROI 2006, Denver.
  • Kawaguchi I, Ishikawa T, Ishibashi M, Irie S, Kakee A. Safety and pharmacokinetics of single oral dose of JTK-303 / GS 9137, a novel HIV integrase inhibitor, in HIV healthy volunteers. Abstract 580, 13th CROI 2006, Denver.
  • Kearney B, Mathias A, Zhong L, et al. Pharmacokinetics / pharmacodynamics of GS-9137 an HIV integrase inhibitor in treatment-naive and experienced patients. Abstract 73, 7th Int Workshop Clin Pharm HIV Therapy 2006, Lisbon, Portugal.
  • Kodama E, Shimura K, Sakagami Y, et al. In vitro antiviral activity and resistance profile of a novel HIV integrase inhibitor JTK-303 / GS-9137. Abstract H-254, 46th ICAAC 2006, San Francisco.
  • Markowitz M, Nguyen BY, Gotuzzo F, et al. Potent antiretroviral effect of MK-0518, a novel HIV-1 integrase inhibitor, as part of combination ART in treatment-naive HIV-1 infected patients. Abstract THLB0214, XVI IAC 2006, Toronto.
  • Matsuzaki Y, Watanabe W, Yamataka K, et al. JTK-303 / GS 9137, a novel small-molecule inhibitor of HIV-1 integrase: anti-HIV activity profile and pharmacokinetics in animals. Abstract 508, 13th CROI 2006, Denver.
  • Mistry C, Wenning A, Merschman S, et al. Atazanavir and ritonavir increase plasma levels of MK-0518. Abstract P291, 8th ICDTHI 2006, Glasgow.

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