Protease inhibitor (pharmacology)

For natural protease inhibitors, see protease inhibitor (biology).

Protease inhibitors (PIs) are a class of antiviral drugs that are widely used to treat HIV/AIDS and hepatitis C. 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.

Protease inhibitors that have been developed and are currently used in clinical practice include:

• Antiretroviral HIV-1 protease inhibitors — class stem –navir
  • amprenavir
  • atazanavir
  • darunavir
  • fosamprenavir
  • indinavir
  • lopinavir
  • nelfinavir
  • ritonavir
  • saquinavir
  • tipranavir
• Hepatitis C virus NS3/4A protease inhibitors — class stem –previr
  • asunaprevir
  • boceprevir
  • grazoprevir
  • paritaprevir
  • simeprevir
  • telaprevir

Given the specificity of the target of these drugs there is the risk, as in 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.

Antiretrovirals

Protease inhibitors were the second class of antiretroviral drugs developed. The first members of this class, saquinavir and ritonavir, 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.

The number of people in the U.S. dying of HIV fell by 60% in the 2 years following the introduction of the first HIV protease inhibitors

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	Abbott	U.S. patent 5,541,206	March 1, 1996	—
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	Abbott	U.S. patent 5,914,332	September 15, 2000	Is only marketed as a fixed-dose combination with ritonavir (see lopinavir/ritonavir).
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. 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. Darunavir is the first drug in a long time that didn't come with a price increase. It leapfrogged 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-protozoals for use against malaria and gastrointestinal protozoal infections:

• A combination of ritonavir and lopinavir was found to have some effectiveness against Giardia 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, 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.

Side effects

Protease inhibitors can cause a syndrome of lipodystrophy, hyperlipidemia, diabetes mellitus type 2, and kidney stones. This lipodystrophy is colloquially known as "Crix belly", after indinavir (Crixivan).

See also

• David Ho — AIDS researcher who pioneered the use of protease inhibitors in treating HIV-infected patients
• The Proteolysis Map
• Reverse transcriptase inhibitor
• Discovery and development of NS5A inhibitors

External links

• A brief history of the development of protease inhibitors by Hoffman La Roche, Abbott, and Merck