cobicistat
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Cobicistat, sold under the brand name Tybost, is a medication for use in the treatment of
human immunodeficiency virus The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause AIDS, acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of th ...
infection (
HIV/AIDS The HIV, human immunodeficiency virus (HIV) is a retrovirus that attacks the immune system. Without treatment, it can lead to a spectrum of conditions including acquired immunodeficiency syndrome (AIDS). It is a Preventive healthcare, pr ...
). Its major mechanism of action is through the inhibition of human CYP3A proteins. Like ritonavir (Norvir), 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.Highleyman, L.
Elvitegravir "Quad" Single-tablet Regimen Shows Continued HIV Suppression at 48 Weeks
. HIV and Hepatitis.com
Cobicistat is a component of three four-drug, fixed-dose combination HIV treatments. The first,
elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil Elvitegravir/cobicistat/emtricitabine/tenofovir, sold under the brand name Stribild, also known as the Quad pill, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. Elvitegravir, emtricitabine and tenofov ...
, 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 Gilead Sciences, Inc. () is an American biopharmaceutical company headquartered in Foster City, California, that focuses on researching and developing antiviral drugs used in the treatment of HIV/AIDS, hepatitis B, hepatitis C, influenza, and CO ...
. The third, cobicistat/darunavir/emtricitabine/tenofovir alafenamide, is marketed as Symtuza and was FDA approved July 17, 2018 and is owned by Janssen Pharmaceuticals. Additionally, there is a fixed-dose combination of cobicistat and the protease inhibitor
darunavir Darunavir (DRV), sold under the brand name Prezista among others, is an antiretroviral medication used to treat and prevent HIV/AIDS. It is generally recommended for use with other antiretrovirals. It is often used with low doses of ritonavir ...
(
darunavir/cobicistat Darunavir/cobicistat, sold under the brand names Prezcobix (US) and Rezolsta (EU), is a fixed-dose combination antiretroviral medication used to treat and prevent HIV/AIDS. It contains darunavir and cobicistat. Darunavir is an HIV protease inhib ...
; marketed as ''Prezcobix'' by Janssen Therapeutics), and a fixed-dose combination of cobicistat and protease inhibitor atazanavir (
atazanavir/cobicistat Atazanavir/cobicistat, sold under the brand name Evotaz, is a fixed-dose combination antiretroviral medication used to treat and prevent HIV/AIDS. It contains atazanavir and cobicistat. Atazanavir is an HIV protease inhibitor and cobicistat i ...
; marketed as ''Evotaz'' by
Bristol-Myers Squibb The Bristol-Myers Squibb Company, doing business as Bristol Myers Squibb (BMS), is an American multinational pharmaceutical company. Headquartered in Princeton, New Jersey, BMS is one of the world's largest pharmaceutical companies and consist ...
). Both Prezcobix and Evotaz were approved by the FDA in January 2015. Cobicistat is a potent inhibitor of
cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...
3A enzymes, including the important
CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...
subtype. It also inhibits intestinal
transport proteins A transport protein (variously referred to as a transmembrane pump, transporter, escort protein, acid transport protein, cation transport protein, or anion transport protein) is a protein that serves the function of moving other materials within ...
, increasing the overall absorption of several HIV medications, including atazanavir,
darunavir Darunavir (DRV), sold under the brand name Prezista among others, is an antiretroviral medication used to treat and prevent HIV/AIDS. It is generally recommended for use with other antiretrovirals. It is often used with low doses of ritonavir ...
, and
tenofovir alafenamide Tenofovir alafenamide, sold under the brand name Vemlidy, is an antiviral medication used against hepatitis B and HIV. It is used for the treatment of chronic hepatitis B virus (HBV) infection in adults with compensated liver disease an ...
.


Chemistry

Cobicistat is a drug analogue of ritonavir, in which the
valine Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deproton ...
moiety is exchanged for a 2-morpholinoethyl group, and the backbone
hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...
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 biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosi ...
in the HIV virus.


Synthesis

Cobicistat may be synthesized from any number of commercially available starting materials. The synthesis shown below utilizes
L-methionine Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other non-essential amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine play ...
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 Gilead Sciences, Inc. () is an American biopharmaceutical company headquartered in Foster City, California, that focuses on researching and developing antiviral drugs used in the treatment of HIV/AIDS, hepatitis B, hepatitis C, influenza, and CO ...
, and successfully optimized ritonavir into a potent CYP3A inhibitor lacking anti-HIV activity. Cobicistat shows potent, selective inhibition of the CYP3A isozyme family ( IC50 0.15 μM) 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 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...
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.PDB 3NXU
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References

{{Portal bar , Medicine , Viruses CYP3A4 inhibitors Thiazoles 4-Morpholinyl compounds Carbamates Ureas Isopropyl compounds Orphan drugs