Protease inhibitor (pharmacology)

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.

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
 * Glecaprevir
 * Paritaprevir
 * Simeprevir
 * Telaprevir
 * 3-chymotrypsin-like protease (including, but not limited to, severe acute respiratory syndrome coronavirus 2) inhibitors—class stem –trelvir
 * Ensitrelvir
 * Nirmatrelvir
 * 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).

Antiretroviral protease inhibitors
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. Most ARPIs are peptide-like molecules which resemble the substrate of the viral protease.

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.



Non-antiretroviral antiviral activity
A drug combination targeting SARS-CoV-2, Paxlovid, was approved in December 2021 to treat COVID-19. 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.

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).