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Protease inhibitors (PIs) are medications that act by interfering with enzymes that cleave proteins. Some of the most well known are antiviral drugs widely used to treat HIV/AIDS, hepatitis C and COVID-19. These protease inhibitors prevent viral replication by selectively binding to viral proteases (e.g. HIV-1 protease) and blocking proteolytic cleavage of protein precursors that are necessary for the production of infectious viral particles.
 | This article needs attention from an expert in Pharmacology. The specific problem is: non-antiviral types in Template:Enzyme inhibition. (January 2020) |
Protease inhibitors that have been developed and are currently used in clinical practice include:
- Antiretroviral HIV-1 protease inhibitors—class stem –navir[1]: 23
- Hepatitis C virus NS3/4A protease inhibitors—class stem –previr[1]: 26
- 3-chymotrypsin-like protease (including, but not limited to, severe acute respiratory syndrome coronavirus 2) inhibitors—class stem –trelvir[2]
Given the specificity of the target of these drugs there is the risk, like with antibiotics, 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 (–mastat) and proteasome inhibitor (–zomib).[1]
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.[4] Most ARPIs are peptide-like molecules which resemble the substrate of the viral protease.[4]
Protease inhibitors were the second class of antiretroviral drugs 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[5] Prior to this the annual death rate had been increasing by approximately 20% each year.
| Name | Trade name | Company | Patent | FDA approval date | Notes |
|---|---|---|---|---|---|
| Saquinavir | Invirase, Fortovase | Hoffmann–La Roche | U.S. patent 5,196,438 | December 6, 1995 | The first protease inhibitor approved by the U.S. Food and Drug Administration (FDA). |
| Ritonavir | Norvir | AbbVie | U.S. patent 5,541,206 | March 1, 1996 | AbbVie was part of Abbott Laboratories when patent was granted. As well as being a protease inhibitor in its own right, ritonavir inhibits the breakdown of other protease inhibitors. This property makes it very useful in drug combinations.[6] |
| Indinavir | Crixivan | Merck & Co. | U.S. patent 5,413,999 | March 13, 1996 | — |
| Nelfinavir | Viracept | Hoffmann–La Roche | U.S. patent 5,484,926 | March 14, 1997 | — |
| Amprenavir | Agenerase | GlaxoSmithKline | U.S. patent 5,585,397 | April 15, 1999 | 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 8 very large gel capsules. Production was discontinued by the manufacturer December 31, 2004, as it has been superseded by fosamprenavir. |
| Lopinavir | Kaletra | AbbVie | U.S. patent 5,914,332 | September 15, 2000 | Is only marketed as a fixed-dose combination with ritonavir (see lopinavir/ritonavir). AbbVie was part of Abbott Laboratories when patent was granted. |
| Atazanavir | Reyataz | Bristol-Myers Squibb | U.S. patent 5,849,911 | 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. |
| Fosamprenavir | Lexiva, Telzir | GlaxoSmithKline | — | October 20, 2003 | A prodrug of amprenavir. 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. |
| Tipranavir | Aptivus | Boehringer Ingelheim | — | June 22, 2005 | Also known as tipranavir disodium. |
| Darunavir | Prezista | Janssen Therapeutics | U.S. patent 6,248,775 | June 23, 2006 | As of 2016, darunavir is an OARAC recommended treatment option for treatment-naïve and treatment-experienced adults and adolescents.[7] Several ongoing phase III trials are showing a high efficiency for the darunavir/ritonavir combination being superior to the lopinavir/ritonavir combination for first-line therapy.[8] Darunavir is the first drug in a long time that did not come with a price increase. It leapfrogged two other approved drugs of its type, and is matching the price of a third.[9][10][11] |
A drug combination targeting SARS-CoV-2, Paxlovid, was approved in December 2021 to treat COVID-19.[12] 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.[13]
Protease inhibitors can cause a syndrome of lipodystrophy, hyperlipidemia, diabetes mellitus type 2, and kidney stones.[14] This lipodystrophy is colloquially known as "Crix belly", after indinavir (Crixivan).[15]
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