Protease inhibitors (PIs) are
medications
A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the medical field and re ...
that act by interfering with
enzymes that cleave proteins. Some of the most well known are
antiviral drugs
Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Unlike most antibiotics, antiviral drugs do n ...
widely used to treat
HIV/AIDS
Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual ...
and
hepatitis C
Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection people often have mild or no symptoms. Occasionally a fever, dark urine, ...
. These protease inhibitors prevent viral replication by selectively binding to viral
proteases
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the for ...
(e.g.
HIV-1 protease
HIV-1 protease (PR) is a retroviral aspartyl protease (retropepsin), an enzyme involved with peptide bond hydrolysis in retroviruses, that is essential for the life-cycle of HIV, the retrovirus that causes AIDS. HIV protease cleaves newly synthe ...
) 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
The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multipl ...
HIV-1 protease
HIV-1 protease (PR) is a retroviral aspartyl protease (retropepsin), an enzyme involved with peptide bond hydrolysis in retroviruses, that is essential for the life-cycle of HIV, the retrovirus that causes AIDS. HIV protease cleaves newly synthe ...
inhibitors—class stem
**
Amprenavir
**
Atazanavir
**
Darunavir
Darunavir (DRV), sold under the brand name Prezista among others, is an antiretroviral medication used to treat and prevent HIV/AIDS. It is generally recommended for use with other antiretrovirals. It is often used with low doses of ritonavir or ...
**
Fosamprenavir
**
Indinavir
**
Lopinavir
Lopinavir is an antiretroviral of the protease inhibitor class. It is used against HIV infections as a fixed-dose combination with another protease inhibitor, ritonavir ( lopinavir/ritonavir).
It was patented in 1995 and approved for medica ...
**
Nelfinavir
**
Ritonavir
Ritonavir, sold under the brand name Norvir, is an antiretroviral drug used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). Ritonavir is a protease inhibitor ...
**
Saquinavir
**
Tipranavir
Tipranavir (TPV), or tipranavir disodium, is a nonpeptidic protease inhibitor (PI) manufactured by Boehringer Ingelheim under the trade name Aptivus . It is administered with ritonavir in combination therapy to treat HIV infection.
Tipranavir ...
*
Hepatitis C virus
The hepatitis C virus (HCV) is a small (55–65 nm in size), enveloped, positive-sense single-stranded RNA virus of the family '' Flaviviridae''. The hepatitis C virus is the cause of hepatitis C and some cancers such as liver cancer (hepatoc ...
NS3/
4A protease inhibitors—class stem
**
Asunaprevir
Asunaprevir (formerly BMS-650032, brand name in Japan and Russia Sunvepra) is an experimental drug candidate for the treatment of hepatitis C. It was undergoing development by Bristol-Myers Squibb and has completed Phase III clinical trials in 201 ...
**
Boceprevir
Boceprevir (INN, trade name Victrelis) is a protease inhibitor used to treat hepatitis caused by hepatitis C virus (HCV) genotype 1. It binds to the HCV nonstructural protein 3 active site.
It was initially developed by Schering-Plough, then b ...
**
Grazoprevir
**
Glecaprevir
**
Paritaprevir
**
Simeprevir
**
Telaprevir
*
Severe acute respiratory syndrome coronavirus 2
Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...
3-chymotrypsin-like protease inhibitors
**
Ensitrelvir
**
Nirmatrelvir
Given the specificity of the target of these drugs there is the risk, like with
antibiotic
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention ...
s, 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 drug
The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multi ...
s developed. The first members of this class,
saquinavir,
ritonavir
Ritonavir, sold under the brand name Norvir, is an antiretroviral drug used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). Ritonavir is a protease inhibitor ...
, 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.
Other activities
Non-antiretroviral antiviral activity
A drug combination targeting SARS-CoV-2 from Pfizer,
Paxlovid, was approved on December 22, 2021. It is a combination of
nirmatrelvir, a protease inhibitor targeted to SARS-CoV-2's
3C-like protease
The 3C-like protease (3CLpro) or main protease (Mpro), formally known as C30 endopeptidase or 3-chymotrypsin-like protease, is the main protease found in coronaviruses. It cleaves the coronavirus polyprotein at eleven conserved sites. It is a ...
, and ritonavir to inhibit nirmatrelvir's metabolism.
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-
protozoa
Protozoa (singular: protozoan or protozoon; alternative plural: protozoans) are a group of single-celled eukaryotes, either free-living or parasitic, that feed on organic matter such as other microorganisms or organic tissues and debris. Histo ...
ls for use against
malaria
Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. ...
and gastrointestinal protozoal infections:
* A combination of ritonavir and lopinavir was found to have some effectiveness against ''
Giardia
''Giardia'' ( or ) is a genus of anaerobic flagellated protozoan parasite
Parasitism is a close relationship between species, where one organism, the parasite, lives on or inside another organism, the host, causing it some harm, and ...
'' infection.
* The drugs saquinavir, ritonavir, and lopinavir have been found to have anti-
malaria
Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. ...
l properties.
* A cysteine protease inhibitor drug was found to cure
Chagas disease
Chagas disease, also known as American trypanosomiasis, is a tropical parasitic disease caused by ''Trypanosoma cruzi''. It is spread mostly by insects in the subfamily '' Triatominae'', known as "kissing bugs". The symptoms change over the co ...
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
A Petri dish (alternatively known as a Petri plate or cell-culture dish) is a shallow transparent lidded dish that biologists use to hold growth medium in which cells can be cultured,R. C. Dubey (2014): ''A Textbook Of Biotechnology For Class-X ...
).
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
Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.
Proteasomes are part of a major mechanism by whi ...
, such as
bortezomib
Bortezomib, sold under the brand name Velcade among others, is an anti-cancer medication used to treat multiple myeloma and mantle cell lymphoma. This includes multiple myeloma in those who have and have not previously received treatment. It is ...
are now front-line drugs for the treatment of
multiple myeloma
Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, ...
.
Tanomastat is one of the
matrix metalloproteinase inhibitor
A matrix metalloproteinase inhibitor (MMPI) inhibits matrix metalloproteinases. As they inhibit cell migration
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic dev ...
s that can be used to treat cancer.
Batimastat
Batimastat (mnemonic: ''batty''-mustard) (INN/USAN, codenamed BB-94) is a drug that was invented by Laurie Hines of British Biotech (now Vernalis). It is an antimetastatic drug that belongs to the family of drugs called angiogenesis inhibitors. ...
was also well known from Lednicer book.
Side effects
Protease inhibitors can cause a syndrome of
lipodystrophy,
hyperlipidemia,
diabetes mellitus type 2
Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urinati ...
, and
kidney stones
Kidney stone disease, also known as nephrolithiasis or urolithiasis, is a crystallopathy where a calculus (medicine), solid piece of material (kidney stone) develops in the urinary tract. Kidney stones typically form in the kidney and leave the ...
. This lipodystrophy is colloquially known as "Crix belly", after
indinavir (Crixivan).
See also
*
The Proteolysis Map
*
Reverse-transcriptase inhibitor
Reverse-transcriptase inhibitors (RTIs) are a class of antiretroviral drugs used to treat HIV infection or AIDS, and in some cases hepatitis B. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase that is required for replicati ...
*
Discovery and development of NS5A inhibitors
*
Discovery and development of HIV-protease inhibitors
References
External links
*
brief historyof the development of protease inhibitors by Hoffman La Roche, Abbott, and Merck
HIV/AIDS Treatment GuidelinesUS Department of Health and Human Services
{{DEFAULTSORT:Protease Inhibitor (Pharmacology)
Protease inhibitors
de:Proteaseinhibitor
fr:Inhibiteur de la protéase