Raltegravir
From Proteopedia
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| - | < | + | <StructureSection load='' size='340' side='right' caption='Raltegravir, better known as Isentress, ([[3l2v]])' scene='Raltegravir/Raltegravir/1'> |
===Better Known as: Isentress=== | ===Better Known as: Isentress=== | ||
* Marketed By: Merck & Co. | * Marketed By: Merck & Co. | ||
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* 2009 Sales: ~$1.1 Billion | * 2009 Sales: ~$1.1 Billion | ||
* Importance: It was the first drug of the Integrase Inhibitor class to be approved by the FDA. It offers a powerful new tool to be utilized in combination therapies against [[HIV]] infections.<ref>PMID:18650512</ref> | * Importance: It was the first drug of the Integrase Inhibitor class to be approved by the FDA. It offers a powerful new tool to be utilized in combination therapies against [[HIV]] infections.<ref>PMID:18650512</ref> | ||
| - | * | + | * See [[Pharmaceutical Drugs]] for more information about other drugs and disorders. |
===Mechanism of Action=== | ===Mechanism of Action=== | ||
[[Retroviral Integrase]] is produced by the HIV retrovirus, enabling [[HIV]] to integrate its genetic material into the [[DNA]] of the infected cell. This integration step effectively transforms the infected cell into a permanent carrier of the viral genome, allowing the virus to persist and proliferate extensively.<ref>PMID:17107277</ref> HIV retroviral integrase forms "intasomes" when it <scene name='Raltegravir/Integrase/1'>complexes with viral DNA</scene>. The integrase domains interact extensively with the viral DNA, <scene name='Raltegravir/Tight_binding/3'>binding the nucleotide chains</scene> precisely within an active site, in close proximity to the predicted target DNA into which the viral DNA will be inserted. Raltegravir binds with great specificity to the HIV integrase active site. It orients itself in such a way as to displace the reactive viral DNA end from the active site almost completely. <scene name='Raltegravir/Raltebound/3'>Raltegravir binds</scene> to residues Asp 128, Asp 185, & Glu 221 via hydrogen bonds, has extensive π-stacking interactions with residues Tyr 212, Pro 214 and the final two nucleotide rings on one viral DNA strand. This disruption prevents the viral DNA from interacting with the target DNA, preventing integration and HIV proliferation.<ref>doi: 10.1038/nature08784</ref><ref>PMID:21030679</ref> | [[Retroviral Integrase]] is produced by the HIV retrovirus, enabling [[HIV]] to integrate its genetic material into the [[DNA]] of the infected cell. This integration step effectively transforms the infected cell into a permanent carrier of the viral genome, allowing the virus to persist and proliferate extensively.<ref>PMID:17107277</ref> HIV retroviral integrase forms "intasomes" when it <scene name='Raltegravir/Integrase/1'>complexes with viral DNA</scene>. The integrase domains interact extensively with the viral DNA, <scene name='Raltegravir/Tight_binding/3'>binding the nucleotide chains</scene> precisely within an active site, in close proximity to the predicted target DNA into which the viral DNA will be inserted. Raltegravir binds with great specificity to the HIV integrase active site. It orients itself in such a way as to displace the reactive viral DNA end from the active site almost completely. <scene name='Raltegravir/Raltebound/3'>Raltegravir binds</scene> to residues Asp 128, Asp 185, & Glu 221 via hydrogen bonds, has extensive π-stacking interactions with residues Tyr 212, Pro 214 and the final two nucleotide rings on one viral DNA strand. This disruption prevents the viral DNA from interacting with the target DNA, preventing integration and HIV proliferation.<ref>doi: 10.1038/nature08784</ref><ref>PMID:21030679</ref> | ||
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===Pharmacokinetics=== | ===Pharmacokinetics=== | ||
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| - | + | {{:Retroviral Integrase Inhibitor Pharmacokinetics}} | |
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===References=== | ===References=== | ||
<references/> | <references/> | ||
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Current revision
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Pharmacokinetics
For Pharmacokinetic Data References, See: References |
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References
- ↑ Steigbigel RT, Cooper DA, Kumar PN, Eron JE, Schechter M, Markowitz M, Loutfy MR, Lennox JL, Gatell JM, Rockstroh JK, Katlama C, Yeni P, Lazzarin A, Clotet B, Zhao J, Chen J, Ryan DM, Rhodes RR, Killar JA, Gilde LR, Strohmaier KM, Meibohm AR, Miller MD, Hazuda DJ, Nessly ML, DiNubile MJ, Isaacs RD, Nguyen BY, Teppler H. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med. 2008 Jul 24;359(4):339-54. PMID:18650512 doi:10.1056/NEJMoa0708975
- ↑ Savarino A. A historical sketch of the discovery and development of HIV-1 integrase inhibitors. Expert Opin Investig Drugs. 2006 Dec;15(12):1507-22. PMID:17107277 doi:10.1517/13543784.15.12.1507
- ↑ 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
- ↑ Hare S, Vos AM, Clayton RF, Thuring JW, Cummings MD, Cherepanov P. Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance. Proc Natl Acad Sci U S A. 2010 Oct 28. PMID:21030679 doi:10.1073/pnas.1010246107
