Protease inhibitor (pharmacology)


Protease inhibitors 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 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:
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, 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.
NameTrade nameCompanyPatentFDA approval dateNotes
SaquinavirInvirase, FortovaseHoffmann–La RocheDecember 6, 1995The first protease inhibitor approved by the U.S. Food and Drug Administration.
RitonavirNorvirAbbVieMarch 1, 1996AbbVie was part of Abbott Laboratories when patent was granted.
IndinavirCrixivanMerck & Co.March 13, 1996—
NelfinavirViraceptHoffmann–La RocheMarch 14, 1997—
AmprenavirAgeneraseGlaxoSmithKlineApril 15, 1999The 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 Production was discontinued by the manufacturer December 31, 2004, as it has been superseded by fosamprenavir.
LopinavirKaletraAbbVieSeptember 15, 2000Is only marketed as a fixed-dose combination with ritonavir. AbbVie was part of Abbott Laboratories when patent was granted.
AtazanavirReyatazBristol-Myers SquibbJune 20, 2003Atazanavir 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.
FosamprenavirLexiva, TelzirGlaxoSmithKline—October 20, 2003A 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.
TipranavirAptivusBoehringer Ingelheim—June 22, 2005Also known as tipranavir disodium.
DarunavirPrezistaJanssen TherapeuticsJune 23, 2006As 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.

Other activities

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:
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. 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. Batimastat was also well-known from Lednicer book.

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.