Retroviral Integrase

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N-terminal and core domain of HIV-1 integrase complex with phosphate, Zn+2 (grey) and K+ (purple) ions (PDB code 1k6y)


Integrase Inhibitors

Name Brand Company Patent Notes
Raltegravir Isentress Merck & Co. - also known as MK-0518. The isopropyl and methyl-oxadiazole of MK-0518 are involved in hydrophobic and stacking interactions with side chains of Pro 214 and Tyr 212 to stabilize this drug within the PFV intasome active site. This manner of drug-binding interaction causes displacement of the reactive 3' viral DNA end from the active site of PFV intasome. After binding of MK-0518 to active site, the reactive 3' hydroxyl group moves away from the active site of the PFV intasome by more than 6 Angstroms. Raltegravir was approved by the FDA on October 12, 2007, for use with other anti-HIV agents in the treatment of HIV infection in adults. It is the first integrase inhibitor approved by the FDA.
Elvitegravir - Gilead Science - GS-9137 interacts with Pro 214 of PFV intasome through its quinolone base and isopropyl group. In experimental stages; shares the core structure of quinolone antibiotics. Phase II studies of elvitegravir in people who are treatment experienced have been completed. Phase III studies in treatment experienced patients are ongoing. A phase II study of elvitegravir in people who have never taken antiretroviral therapy is underway. This study will also be evaluated a boosting agent in place of Norvir, currently called GS9350. Elvitegravir holds promise for HIV-positive patients who have taken other anti-HIV drugs in the past.
MK-2048 - Merck & Co. - A second generation integrase inhibitor, intended to be used against HIV infection. It is superior to the first available integrase inhibitor, raltegravir, in that it inhibits the HIV enzyme integrase 4 times longer. It is being investigated for use as part of pre-exposure prophylaxis (PrEP).

See also Retroviral Integrase Inhibitor Pharmacokinetics[6].

Additional Resources

For additional information, see: Human Immunodeficiency Virus

3D Structures of Retroviral Integrase

Updated on 27-September-2017


References

  1. Pandey KK, Grandgenett DP. HIV-1 Integrase Strand Transfer Inhibitors: Novel Insights into their Mechanism of Action. Retrovirology (Auckl). 2008 Nov 5;2:11-16. PMID:19915684
  2. 2.0 2.1 2.2 2.3 Hare S, Gupta SS, Valkov E, Engelman A, Cherepanov P. Retroviral intasome assembly and inhibition of DNA strand transfer. Nature. 2010 Mar 11;464(7286):232-6. Epub 2010 Jan 31. PMID:20118915 doi:10.1038/nature08784
  3. deJesus, Edwin HIV Antiretroviral Agents in Development. The Body: The Complete HIV/AIDS Resource. March 30, 2006
  4. Braun, J.F., Cronje, R.J and Henderson, M.G. HIV-1 Integrase Inhibitors Inhibitors (2008). www.prn.org Volume 13, Pages 1–9
  5. AIDS-Info
  6. Iwamoto M, Wenning LA, Petry AS, Laethem M, De Smet M, Kost JT, Breidinger SA, Mangin EC, Azrolan N, Greenberg HE, Haazen W, Stone JA, Gottesdiener KM, Wagner JA. Minimal effects of ritonavir and efavirenz on the pharmacokinetics of raltegravir. Antimicrob Agents Chemother. 2008 Dec;52(12):4338-43. Epub 2008 Oct 6. PMID:18838589 doi:10.1128/AAC.01543-07

Further Reading

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