protease inhibitors
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Protease inhibitors (PIs) are
medications Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...
that act by interfering with enzymes that cleave proteins. Some of the most well known are antiviral drugs widely used to treat
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 ...
,
hepatitis C Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection period, people often have mild or no symptoms. Early symptoms can include ...
and
COVID-19 Coronavirus disease 2019 (COVID-19) is a contagious disease caused by the coronavirus SARS-CoV-2. In January 2020, the disease spread worldwide, resulting in the COVID-19 pandemic. The symptoms of COVID‑19 can vary but often include fever ...
. These protease inhibitors prevent viral replication by selectively binding to viral proteases (e.g.
HIV-1 protease HIV-1 protease or PR is a retroviral aspartyl protease (retropepsin), an enzyme involved with peptide bond hydrolysis in retroviruses, that is essential for the life-cycle of HIV, the retrovirus that causes AIDS. HIV-1 PR cleaves newly synthesized ...
) and blocking proteolytic cleavage of protein precursors that are necessary for the production of infectious viral particles. Protease inhibitors that have been developed and are currently used in clinical practice include: *
Antiretroviral The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of mu ...
HIV-1 protease HIV-1 protease or PR is a retroviral aspartyl protease (retropepsin), an enzyme involved with peptide bond hydrolysis in retroviruses, that is essential for the life-cycle of HIV, the retrovirus that causes AIDS. HIV-1 PR cleaves newly synthesized ...
inhibitors—class stem ** Amprenavir ** 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 ...
** Fosamprenavir ** Indinavir ** Lopinavir **
Nelfinavir Nelfinavir, sold under the brand name Viracept, is an antiretroviral medication used in the treatment of HIV/AIDS. Nelfinavir belongs to the class of drugs known as protease inhibitor (pharmacology), protease inhibitors (PIs) and like other PIs ...
** Ritonavir ** Saquinavir ** Tipranavir * Hepatitis C virus NS3/ 4A protease inhibitors—class stem ** Asunaprevir ** Boceprevir ** Grazoprevir ** Glecaprevir ** Paritaprevir ** Simeprevir ** Telaprevir ** Voxilaprevir * 3-chymotrypsin-like protease (including, but not limited to,
severe acute respiratory syndrome coronavirus 2 Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19, the respiratory illness responsible for the COVID-19 pandemic. The virus previously had the Novel coronavirus, provisional nam ...
) inhibitors—class stem ** Ensitrelvir ** Nirmatrelvir ** Simnotrelvir * Given the specificity of the target of these drugs there is the risk, like with
antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy ...
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. In addition to those non-human proteases listed above, inhibitors of human proteases may be used to treat cancer. See the articles matrix metalloproteinase inhibitor () and proteasome inhibitor ().


Antiretroviral protease inhibitors

Antiretroviral protease inhibitors act by binding to the catalytic site of HIV protease, preventing cleavage of viral polyprotein precursor proteins into functional viral proteins required for viral replication. Most ARPIs are peptide-like molecules which resemble the substrate of the viral protease. Protease inhibitors were the second class of
antiretroviral drug The management of HIV/AIDS normally includes the use of multiple Antiviral drug, antiretroviral drugs as a strategy to control HIV/AIDS, HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV li ...
s developed. The first members of this class, saquinavir, ritonavir, and indinavir, were approved in late 1995–1996. Within 2 years, annual deaths from AIDS in the United States fell from over 50,000 to approximately 18,000 Prior to this the annual death rate had been increasing by approximately 20% each year.


Non-antiretroviral antiviral activity

A drug combination targeting SARS-CoV-2, Paxlovid, was approved in December 2021 to treat COVID-19. It is a combination of nirmatrelvir, a protease inhibitor targeted to the SARS-CoV-2 3C-like protease, and ritonavir, which inhibits the metabolism of nirmatrelvir, thereby prolonging its effect.


Side effects

Protease inhibitors can cause a syndrome of
lipodystrophy Lipodystrophy syndromes are a group of genetic or acquired disorders in which the body is unable to produce and maintain healthy fat tissue. The medical condition is characterized by abnormal or degenerative conditions of the body's adipose tissu ...
,
hyperlipidemia Hyperlipidemia is abnormally high levels of any or all lipids (e.g. fats, triglycerides, cholesterol, phospholipids) or lipoproteins in the blood. citing: and The term ''hyperlipidemia'' refers to the laboratory finding itself and is also use ...
, diabetes mellitus type 2, and
kidney stones Kidney stone disease (known as nephrolithiasis, renal calculus disease, or urolithiasis) is a crystallopathy and occurs when there are too many minerals in the urine and not enough liquid or hydration. This imbalance causes tiny pieces of cr ...
. This lipodystrophy is colloquially known as "Crix belly", after indinavir (Crixivan).


See also

* The Proteolysis Map * Reverse-transcriptase inhibitor * Discovery and development of NS5A inhibitors * Discovery and development of HIV-protease inhibitors


References


External links

*
brief history
of the development of protease inhibitors by Hoffman La Roche, Abbott, and Merck
HIV/AIDS Treatment Guidelines
US Department of Health and Human Services {{DEFAULTSORT:Protease Inhibitor (Pharmacology) Protease inhibitors de:Proteaseinhibitor fr:Inhibiteur de la protéase