Cobicistat Cobicistat , sold under the brand name Tybost , is a medication for use in the treatment of human immunodeficiency virus infection . Its major mechanism of action is through the inhibition of human CYP3A proteins. Like ritonavir , cobicistat is of interest for its ability to inhibit liver enzymes that metabolize other medications used to treat HIV, notably elvitegravir , an HIV integrase inhibitor . By combining cobicistat with elvitegravir, higher concentrations of the latter are achieved in the body with lower dosing, theoretically enhancing elvitegravir's viral suppression while diminishing its adverse side-effects. In contrast with ritonavir, the only other booster approved for use as a part of HAART , cobicistat has no anti-HIV activity of its own. Cobicistat is a component of three four-drug, fixed-dose combination HIV treatments. The first, elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil , is marketed as Stribild and was approved by the FDA in August 2012 for use in the United States . The second, elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide , is marketed as Genvoya and was approved by the FDA in November 2015 for use in the United States. Both Stribild and Genvoya are owned by Gilead Sciences . The third, cobicistat, darunavir , emtricitabine, and tenofovir alafenamide , is marketed as Symtuza and was FDA approved July 17 , 2018 and is owned by Janssen Pharmaceuticals . Additionally, in existence are a fixed-dose combination of cobicistat and protease inhibitor darunavir, and a fixed-dose combination of cobicistat and protease inhibitor atazanavir . Both Prezcobix and Evotaz were approved by the FDA in January 2015 . Cobicistat is a potent inhibitor of cytochrome P450 3A enzymes, including the important CYP3A4 subtype. It also inhibits intestinal transport proteins , increasing the overall absorption of several HIV medications , including atazanavir, darunavir, and tenofovir alafenamide.Chemistry Cobicistat is a drug analogue of ritonavir, in which the valine moiety is exchanged for a 2-morpholinoethyl group, and the backbone hydroxyl group is removed. These changes effectively eliminate the anti-HIV activity of ritonavir while preserving its inhibitory effects on the CYP3A isozyme family of proteins . Cobicistat is therefore able to increase plasma concentration of other coadministered anti-HIV drugs without the risk of causing cobicistat-resistant mutations in the HIV virus .Synthesis Cobicistat may be synthesized from any number of commercially available starting materials. The synthesis shown below utilizes L-methionine and bromoacetic acid as starting materials.Discovery and development Cobicistat was developed through structure-activity relationship studies using ritonavir and desoxyritonavir as lead compounds . These studies were conducted by scientists at Gilead Sciences, and successfully optimized ritonavir into a potent CYP3A inhibitor lacking anti-HIV activity. Cobicistat shows potent, selective inhibition of the CYP3A isozyme family compared to some CYP1A and CYP2C isozymes. As cobicistat was discovered using structure-activity relationship studies, its CYP3A binding is still poorly understood; however, research on the protein-ligand interactions between CYP3A4 and ritonavir analogues demonstrates that CYP 3A4 residues Ile369 , Ala370 , Met371 , as well as Arg105 and Ser119 , play an important role in ritonavir analogue inhibition of CYP3A4.
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