Protease inhibitor (pharmacology)
Encyclopedia
Protease inhibitors are a class of drugs used to treat or prevent infection
by virus
es, including HIV
and Hepatitis C
. PIs prevent viral replication by inhibiting the activity of proteases, e.g.HIV-1 protease
, enzyme
s used by the viruses to cleave nascent protein
s for final assembly of new virions.
Protease inhibitors have been developed or are presently undergoing testing for treating various viruses:
Given the specificity of the target of these drugs there is the risk, as in antibiotic
s, of the development of drug-resistant mutated viruses. To reduce this risk it is common to use several different drugs together that are each aimed at different targets.
s developed. In all cases, patents remain in force until 2010 or beyond.
ls for use against malaria and gastrointestinal protozoal infections:
Inhibitors of the proteasome
, such as Velcade/Bortezomib
are now front-line drugs for the treatment of various cancers, notably Multiple Myeloma
.
, hyperlipidaemia and diabetes mellitus type 2
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
by virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
es, including HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
and Hepatitis C
Hepatitis C
Hepatitis C is an infectious disease primarily affecting the liver, caused by the hepatitis C virus . The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years...
. PIs prevent viral replication by inhibiting the activity of proteases, e.g.HIV-1 protease
HIV-1 protease
HIV-1 protease is a retroviral aspartyl protease that is essential for the life-cycle of HIV, the retrovirus that causes AIDS.HIV PR cleaves newly synthesized polyproteins at the appropriate places to create the mature protein components of an infectious HIV virion...
, enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s used by the viruses to cleave nascent protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s for final assembly of new virions.
Protease inhibitors have been developed or are presently undergoing testing for treating various viruses:
- HIVHIVHuman immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
/AIDSAIDSAcquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
: antiretroviralAntiretroviral drugAntiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. When several such drugs, typically three or four, are taken in combination, the approach is known as Highly Active Antiretroviral Therapy, or HAART...
protease inhibitors (saquinavirSaquinavirSaquinavir is an antiretroviral drug used in HIV therapy. It falls in the protease inhibitor class. Two formulations have been marketed:*a hard-gel capsule formulation of the mesylate, with trade name Invirase, which requires combination with ritonavir to increase the saquinavir bioavailability;*a...
, ritonavirRitonavirRitonavir, with trade name Norvir , is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS....
, indinavirIndinavirIndinavir is a protease inhibitor used as a component of highly active antiretroviral therapy to treat HIV infection and AIDS.-History:...
, nelfinavirNelfinavirNelfinavir is an antiretroviral drug used in the treatment of the human immunodeficiency virus . Nelfinavir belongs to the class of drugs known as protease inhibitors and like other PIs is generally used in combination with other antiretroviral drugs.Nelfinavir mesylate is a potent and orally...
, amprenavir etc.) - Hepatitis CHepatitis CHepatitis C is an infectious disease primarily affecting the liver, caused by the hepatitis C virus . The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years...
: BoceprevirBoceprevirBoceprevir is a protease inhibitor used as a treatment for hepatitis C genotype 1. It binds to HCV nonstructural 3 active site.... - Hepatitis C: TelaprevirTelaprevirTelaprevir , marketed as the brand name Incivek, is a pharmaceutical drug for the treatment of hepatitis C co-developed by Vertex and Johnson & Johnson. It is a member of a class of antiviral drugs known as protease inhibitors...
Given the specificity of the target of these drugs there is the risk, as in antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
s, of the development of drug-resistant mutated viruses. To reduce this risk it is common to use several different drugs together that are each aimed at different targets.
Antiretrovirals
Protease inhibitors were the second class of antiretroviral drugAntiretroviral drug
Antiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. When several such drugs, typically three or four, are taken in combination, the approach is known as Highly Active Antiretroviral Therapy, or HAART...
s developed. In all cases, patents remain in force until 2010 or beyond.
| Name | Trade name | Company | Patent | Notes >- | Saquinavir Saquinavir Saquinavir is an antiretroviral drug used in HIV therapy. It falls in the protease inhibitor class. Two formulations have been marketed:*a hard-gel capsule formulation of the mesylate, with trade name Invirase, which requires combination with ritonavir to increase the saquinavir bioavailability;*a... |
Fortovase, Invirase | Hoffmann–La Roche | FDA Food and Drug Administration The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments... (December 6, 1995). >- | Ritonavir Ritonavir Ritonavir, with trade name Norvir , is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS.... |
Norvir | Abbott Laboratories Abbott Laboratories Abbott Laboratories is an American-based global, diversified pharmaceuticals and health care products company. It has 90,000 employees and operates in over 130 countries. The company headquarters are in Abbott Park, North Chicago, Illinois. The company was founded by Chicago physician, Dr.... |
>- | Crixivan | Merck & Co. Merck & Co. Merck & Co., Inc. , also known as Merck Sharp & Dohme or MSD outside the United States and Canada, is one of the largest pharmaceutical companies in the world. The Merck headquarters is located in Whitehouse Station, New Jersey, an unincorporated area in Readington Township... |
>- | Viracept | Agouron Pharmaceuticals | >- | Agenerase | GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom... |
>- | Kaletra | Abbott Abbott Laboratories Abbott Laboratories is an American-based global, diversified pharmaceuticals and health care products company. It has 90,000 employees and operates in over 130 countries. The company headquarters are in Abbott Park, North Chicago, Illinois. The company was founded by Chicago physician, Dr.... |
- | ritonavir Ritonavir Ritonavir, with trade name Norvir , is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS.... . >- | Atazanavir Atazanavir Atazanavir, marketed under the trade name Reyataz by Bristol Myers, is an antiretroviral drug of the protease inhibitor class... |
Reyataz | Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb , often referred to as BMS, is a pharmaceutical company, headquartered in New York City. The company was formed in 1989, following the merger of its predecessors Bristol-Myers and the Squibb Corporation... |
- | less likely to cause lipodystrophy and elevated cholesterol as side effects. It may also not be cross-resistant with other PIs. >- | Fosamprenavir Fosamprenavir Fosamprenavir , under the trade names Lexiva and Telzir is a pro-drug of the protease inhibitor and antiretroviral drug amprenavir. The FDA approved it October 20, 2003, while the EMEA approved it on July 12, 2004... |
Lexiva, Telzir | GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom... |
- | prodrug Prodrug A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and... 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 Slow-release Slow-release is a strategy in material science in which a chemical compound is introduced into a system at a reduced speed. Slow-release is applied in fertilizers, pesticides and drugs.... version of amprenavir and thus reduces the number of pills required versus standard amprenavir. >- | Tipranavir Tipranavir Tipranavir, or tipranavir disodium, is a nonpeptidic protease inhibitor manufactured by Boehringer-Ingelheim under the trade name Aptivus... |
Aptivus | Boehringer-Ingelheim Boehringer-Ingelheim C.H. Boehringer Sohn AG & Ko. KG is the parent company of Boehringer Ingelheim, which was founded in 1885 by Albert Boehringer in Ingelheim am Rhein. The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally... |
- | >- | Prezista | Tibotec Tibotec Tibotec is a pharmaceutical company with a focus on research and development for the treatment of infectious diseases such as HIV , and Hepatitis C... |
- | It was approved by the Food and Drug Administration Food and Drug Administration The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments... (FDA) on June 23, 2006. Prezista is an OARAC OARAC OARAC is the abbreviation for the Office of AIDS Research Advisory Council, which is developing guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents.... recommended treatment option for treatment-naïve and treatment-experienced adults and adolescents. Several ongoing phase III trials are showing a high efficiency for the PREZISTA/rtv Ritonavir Ritonavir, with trade name Norvir , is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS.... combination being superior to the lopinavir Lopinavir Lopinavir is an antiretroviral of the protease inhibitor class. It is used as a fixed-dose combination with another protease inhibitor, ritonavir, under the trade names Kaletra and Aluvia .... /rtv Ritonavir Ritonavir, with trade name Norvir , is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS.... combination for first-line therapy. Darunavir is the first drug in a long time that didn't come with a price increase. It leapfrogged Leapfrogging The concept of leapfrogging was originally used in the context of economic growth theories and industrial-organization innovation studies with specific focus on competition among firms. It is based on Joseph Schumpeter's notion of ‘gales of creative destruction’... two other approved drugs of its type, and is matching the price of a third. |
Antiprotozoal Activity
Researchers are investigating the use of protease inhibitors developed for HIV treatment as anti-protozoaProtozoa
Protozoa are a diverse group of single-cells eukaryotic organisms, many of which are motile. Throughout history, protozoa have been defined as single-cell protists with animal-like behavior, e.g., movement...
ls for use against malaria and gastrointestinal protozoal infections:
- A combination of ritonavir and lopinavir was found to have some effectiveness against GiardiaGiardiaGiardia is a genus of anaerobic flagellated protozoan parasites of the phylum Metamonada in the supergroup "Excavata" that colonise and reproduce in the small intestines of several vertebrates, causing giardiasis, commonly known as Beaver fever...
infection. - The drugs saquinavir, ritonavir, and lopinavir have been found to have anti-malarial properties.
- A cysteine protease inhibitor drug was found to cure Chagas disease in mice.
Anticancer Activity
Researchers are investigating whether protease inhibitors could possibly be used to treat cancer. For example, nelfinavir and atazanavir are able to kill tumor cells in culture (in a Petri dish). This effect has not yet been examined in humans; but studies in laboratory mice have shown that nelfinavir is able to suppress the growth of tumors in these animals, which represents a promising lead towards testing this drug in humans as well.Inhibitors of the proteasome
Proteasome
Proteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...
, such as Velcade/Bortezomib
Bortezomib
Bortezomib is the first therapeutic proteasome inhibitor to be tested in humans. It is approved in the U.S. for treating relapsed multiple myeloma and mantle cell lymphoma...
are now front-line drugs for the treatment of various cancers, notably Multiple Myeloma
Multiple myeloma
Multiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...
.
Side Effects
Protease inhibitors can cause a syndrome of lipodystrophyLipodystrophy
Lipodystrophy is a medical condition characterized by abnormal or degenerative conditions of the body's adipose tissue. A more specific term, lipoatrophy is used when describing the loss of fat from one area...
, hyperlipidaemia and diabetes mellitus type 2
Diabetes mellitus type 2
Diabetes mellitus type 2formerly non-insulin-dependent diabetes mellitus or adult-onset diabetesis a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and...
See also
- David Ho - AIDS researcher who pioneered the use of protease inhibitors in treating HIV-infected patients
- The Proteolysis MapThe Proteolysis MapThe Proteolysis MAP is an integrated web resource focused on proteases.-Rationale:PMAP is to aid the protease researchers in reasoning about proteolytic networks and metabolic pathways.-History and funding:...
- Reverse transcriptase inhibitorReverse transcriptase inhibitorReverse-transcriptase inhibitors are a class of antiretroviral drug used to treat HIV infection, tumors, and cancer. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase enzyme that retroviruses need to reproduce.-Mechanism:...
External links
- A brief history of the development of protease inhibitors by Hoffman La Roche, Abbott, and Merck