Protease inhibitor (pharmacology)
This article needs attention from an expert in Pharmacology. The specific problem is: non-antiviral types in Template:Enzyme inhibition. (January 2020) |
Protease inhibitors (PIs) are
Protease inhibitors that have been developed and are currently used in clinical practice include:
- Antiretroviral HIV-1 protease inhibitors—class stem –navir[1]: 23
- 4A protease inhibitors—class stem –previr[1]: 26
- severe acute respiratory syndrome coronavirus 2) inhibitors—class stem –trelvir[2]
- Ensitrelvir
- Nirmatrelvir[3]
- Simnotrelvir
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]
Antiretrovirals
Protease inhibitors were the second class of
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.[5] |
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 Production was discontinued by the manufacturer December 31, 2004, as it has been superseded by fosamprenavir.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 slow release version of amprenavir and thus reduces the number of pills required versus standard amprenavir.
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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.[6] 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.[7] 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.[8][9][10]
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Other activities
Non-antiretroviral antiviral activity
A drug combination targeting SARS-CoV-2 from Pfizer,
Protease inhibitors also are used to treat Hepatitis C.
Antiprotozoal activity
Researchers are investigating the use of protease inhibitors developed for HIV treatment as anti-protozoals for use against malaria and gastrointestinal protozoal infections:
- A combination of ritonavir and lopinavir was found to have some effectiveness against Giardia infection.[13]
- The drugs saquinavir, ritonavir, and lopinavir have been found to have anti-malarial properties.[14]
- A cysteine protease inhibitor drug was found to cure Chagas disease in mice.[15]
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).[16][17] 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.[17]
Inhibitors of the proteasome, such as bortezomib are now front-line drugs for the treatment of multiple myeloma.
Tanomastat is one of the matrix metalloproteinase inhibitors that can be used to treat cancer. Batimastat was also well known from Lednicer book.
Side effects
Protease inhibitors can cause a syndrome of
See also
- The Proteolysis Map
- Reverse-transcriptase inhibitor
- Discovery and development of NS5A inhibitors
- Discovery and development of HIV-protease inhibitors
References
- ^ a b c "The Use of Stems in the Selection of International Nonproprietary Names (INN) for Pharmaceutical Substances" (PDF). World Health Organization. Retrieved 5 November 2016.
- ^ Programme on International Nonproprietary Names (INN) (February 2023). "Pre-stems: Suffixes used in the selection of INN - February 2023". World Health Organization.
- PMID 34502033.
- ^ "HIV Surveillance --- United States, 1981--2008". Retrieved 8 November 2013.
- ISBN 9780857111562.
- ^ "Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents" (PDF). Developed by the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents—A Working Group of the Office of AIDS Research Advisory Council (OARAC). July 14, 2016. Retrieved 5 November 2016.
- S2CID 26084893.
- ^ Liz Highleyman, Patient Advocates Commend Pricing of New PI Darunavir, http://www.hivandhepatitis.com/recent/2006/ad1/063006_a.html
- ^ Darunavir - first molecule to treat drug-resistant HIV
- .
- ^ "FDA authorizes 1st antiviral pill for COVID --- United States, 2021". NPR. Retrieved 22 December 2021.
- ^ Woodley M (19 October 2021). "What is Australia's potential new COVID treatment?". The Royal Australian College of General Practitioners (RACGP). Retrieved 6 November 2021.
- PMID 17137752.
- PMID 16436721.
- PMID 17698625.
- PMID 17785575.
- ^ PMID 18006837.
- PMID 12626882.
- PMID 11364559.
External links
- A 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