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 caused by hepatitis C virus. Protease inhibitors prevent viral replication 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 have been developed or are presently undergoing testing for treating various viruses:

• HIV/AIDS: antiretroviral protease inhibitors (saquinavir, ritonavir, indinavir, nelfinavir, amprenavir etc.)
• Hepatitis C: boceprevir, telaprevir , simeprevir

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 (Hoffman-La Roche) and ritonavir (Abbott), 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.

Name	Trade name	Company	Patent	Notes
Saquinavir	Fortovase, Invirase	Hoffmann–La Roche	U.S. Patent 5,196,438	It was the first protease inhibitor approved by the FDA (December 6, 1995).
Ritonavir	Norvir	Abbott Laboratories	U.S. Patent 5,541,206	-
Indinavir	Crixivan	Merck & Co.	U.S. Patent 5,413,999	-
Nelfinavir	Viracept	Agouron Pharmaceuticals	U.S. Patent 5,484,926	-
Amprenavir	Agenerase	GlaxoSmithKline	U.S. Patent 5,585,397	The FDA approved it April 15, 1999, making it 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 eight 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 Production was discontinued by the manufacturer December 31, 2004, as it has been superseded by fosamprenavir.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	Is only marketed as a combination, with ritonavir.
Atazanavir	Reyataz	Bristol-Myers Squibb	U.S. Patent 5,849,911	The FDA approved it on 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	-	Is a prodrug 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 version of amprenavir and thus reduces the number of pills required versus standard amprenavir.
Tipranavir	Aptivus	Boehringer-Ingelheim	-	Also known as tipranavir disodium
Darunavir	Prezista	Tibotec	U.S. Patent 6,248,775	It was approved by the Food and Drug Administration (FDA) on June 23, 2006. Prezista 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 PREZISTA/rtv combination being superior to the lopinavir/rtv 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.
Simeprevir	Olysio, formerly TMC435	Medivir & Johnson & Johnson	U.S. Patent 7,671,032	Simeprevir is a NS3/4A protease inhibitor

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 Velcade/Bortezomib are now front-line drugs for the treatment of various cancers, notably Multiple Myeloma.

Side effects

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

External links

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