Retroviral Integrase

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| [[Atazanavir]] || Reyataz || [[Bristol-Myers Squibb]] || - || The FDA approved it on June 20, 2003. Atazanavir was the first PI approved for once-daily dosing. It appears to be less likely to cause lipodystrophy and elevated cholesterol as side effects. It may also not be cross-resistant with other PIs.
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| [[Raltegravir]] || Isentress || [[Merck & Co.]] || - || also known as MK-0518. 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.
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| [[Amprenavir]] || Agenerase || [[GlaxoSmithKline]] || {{US patent|5585397}} || The FDA approved it April 15, 1999, making it the sixteenth FDA-approved antiretroviral. It was the first protease inhibitor approved for twice-a-day dosing instead of needing to be taken every eight hours. The convenient dosing came at a price, as the dose required is 1,200 mg, delivered in eight very large gel capsules. Production was discontinued by the manufacturer December 31, 2004, as it has been superseded by fosamprenavir.
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| [[Darunavir]] || Prezista || [[Tibotec]] || - || It was approved by the [[Food and Drug Administration]] (FDA) on June 23, 2006. Prezista is an [[OARAC]] recommended treatment option for treatment-naïve and treatment-experienced adults and adolescents<ref name="oarac">Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, November 3, 2008, Developed by the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents – A Working Group of the Office of AIDS Research Advisory Council (OARAC). [http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf full guidelines].</ref>. Several ongoing [[Clinical trial#Phase III|phase III]] trials are showing a high efficiency for the PREZISTA/[[ritonavir|rtv]] combination being superior to the [[lopinavir]]/[[ritonavir|rtv]] combination for first-line therapy.<ref>{{cite journal |author=Madruga JV, Berger D, McMurchie M, ''et al.'' |title=Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial |journal=Lancet |volume=370 |issue=9581 |pages=49–58 |year=2007 |month=Jul |pmid=17617272 |doi=10.1016/S0140-6736(07)61049-6 |url=}}</ref> Darunavir is the first drug in a long time that didn't come with a price increase. It [[leapfrogging|leapfrogged]] two other approved drugs of its type, and is matching the price of a third.<ref>Liz Highleyman, Patient Advocates Commend Pricing of New PI Darunavir, http://www.hivandhepatitis.com/recent/2006/ad1/063006_a.html</ref><ref>[Darunavir - first molecule to treat drug-resistant HIV, http://www.news-medical.net/?id=19211]</ref><ref>{{cite journal |author=Borman S |title=Retaining Efficacy Against Evasive HIV: Darunavir analog to AIDS-virus shapeshifters: Resistance may be futile |journal=Chemical & Engineering News |volume=84 |issue=34 |pages=9 |year=2006 |url=http://pubs.acs.org/cen/news/84/i34/8434drugdesign.html }}</ref>
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| [[Fosamprenavir]]|| Lexiva, Telzir || [[GlaxoSmithKline]] || - || Is a [[prodrug]] of amprenavir. The FDA approved it October 20, 2003. The human body metabolizes fosamprenavir in order to form amprenavir, which is the active ingredient. That metabolization increases the duration that amprenavir is available, making fosamprenavir a [[slow-release]] version of amprenavir and thus reduces the number of pills required versus standard amprenavir.
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| [[Indinavir]] || Crixivan || [[Merck & Co.]] || {{US patent|5413999}} || -
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| [[Lopinavir]] || Kaletra || [[Abbott Laboratories|Abbott]] || - || Is only marketed as a combination, with [[ritonavir]].
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| [[Nelfinavir]] || Viracept || [[Agouron Pharmaceuticals]] || {{US patent|5484926}} || -
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| [[Elvitegravir]] || GS-9137 || [[Gilead Science]] || - || in experimental stages. 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.
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| [[Ritonavir]] || Norvir || [[Abbott Laboratories]] || {{US patent|5541206}} || -
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| [[Saquinavir]] || Fortovase, Invirase || [[Hoffmann–La Roche]] || {{US patent|5196438}} || It was the first protease inhibitor approved by the [[Food and Drug Administration|FDA]] (December 6, 1995).
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| [[Tipranavir]] || Aptivus || [[Boehringer-Ingelheim]] || - || Also known as tipranavir disodium
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==References==
==References==

Revision as of 03:13, 14 February 2010

Contents

Introduction

Integrase is an essential retroviral enzyme that binds to viral DNA and inserts it into a host cell chromosome. [The reverse transcribed cDNA of human immunodeficiency virus type 1 (HIV-1) is inserted in the host cell genome in order increase pathogen fitness and virulence.]It is produced by a class of retrovirus (like HIV) and is used by the virus to incorporate its genetic material into the host cell DNA. The host cellular machinery then produces mRNA and then protein from the incorporated genetic material, thus replicating the virus. Although several integrase inhibiting drugs have been investigated, the mechanism [responsible for strand-transfer inhibition action remain unclear] of action was not clear. On February 1, 2010, a crystal structure of the PFV Intasome was published, paving the way for better retroviral treatments. [However, Hare et al (2010) determined the structural constituents of retroviral integration. Further elucidation of the complete structure of the retroviral integrase, and its application to regulate functional and enzymatic activities could potentially enable researchers to delay the progression of retroviral diseases. Moreover, study of HIV-1 integration could lead to a promising new target, and contribute to the generation pharmacophore models for antiviral therapy. ]

HIV Integrase inhibitors: Raltegravir, marketed as Isentress is currently approved as a therapeutic inhibitor of HIV integrase. It was approved on October 12, 2007. [link below has a table of antiretroviral drugs with trade name, company, patents, and notes]

Impact of Structure

HIV protease structure is among the highest ranked structures that have contributed to saving many lives and added to the quality of life of many HIV-afflicted individuals. It is implemented in structure-based drug design to develop anti-retroviral protease inhibitors, and is used as a significant component of highly active anti-retroviral therapy (HAART). While HAART improves the quality of life as well as extending the life of many patients, it fails to eradicate the disease. For more, please see AIDS Before Protease Inhibitors & HIV Protease Inhibitors: A Breakthrough.

PFV Crystallization

To mimic the viral DNA ends of HIV-1, Hare et al (2010) utilized soluble and fully functional prototype foamy virus (PFV) intasome preparations, obtained using recombinant PFV integrase and double-stranded oligonucleotides.

The remarkable stability of the integrase-DNA complexes were determined by observing the in vitro strand transfer reactions, which were classified into three modes of deproteination migration: (1) single concerted events: linearized target plasmid; (2) multiple concerted events: smear; (3) half-site events: open circular DNA. Further characterization of the PFV intasome also exhibited structural substantiality which implied strong protein-protein and protein-DNA interactions despite prolonged incubation under high ionic strength conditions. Comprehensive crystallization assays effected a viable crystal configuration that diffracted X-rays to 2.9 Angstroms resolution. A three-dimensional structure was ultimately determined. The asymmetric unit contained a single integrase dimer with a stably bound viral DNA molecule, and a pair of integrase dimers consociated with symmetry, which formed an oblong tetramer. The dimer interface is stabilized by intermolecular amino terminal and catalytic core domains (inner subunit-outer subunit) interactions. The overall shape of the oblong tetramer is unique albeit bearing semblances to previously reported HIV-1 integrase complexes.

Overall Architecture & Components

Active Site

Mechanism for strand-transfer inhibition action

Antiretrovirals

References

1.Hare, Stephen; Gupta, Saumya Shree; Valkov, Eugene; Engelman, Alan & Cherepanov, Peter (2010) Retroviral intasome assembly and inhibition of DNA strand transfer. Nature 2010/01/31/online doi:10.1038/nature08784 <http://www.nature.com/nature/journal/vaop/ncurrent/full/nature08784.html> Template:STRUCTURE 3l2q

2. http://www.isentress.com/raltegravir/isentress/consumer/index.jsp

Further Reading

Name Trade name Company Patent Notes
Raltegravir Isentress Merck & Co. - also known as MK-0518. 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 GS-9137 Gilead Science - in experimental stages. 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.
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