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{{Short description|Class of antiviral drugs used to treat HIV/AIDS and hepatitis C}}{{for multi|natural protease inhibitors|Protease inhibitor (biology)}}{{Expert needed|1=Pharmacology|reason=non-antiviral types in |date=January 2020}}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:{{div col|colwidth=30em}}

• Antiretroviral HIV-1 protease inhibitors—class stem {{not a typo|–navir}}WEB, The Use of Stems in the Selection of International Nonproprietary Names (INN) for Pharmaceutical Substances,weblink World Health Organization, 5 November 2016, {{rp|23}}
  • Amprenavir
  • Atazanavir
  • Darunavir
  • Fosamprenavir
  • Indinavir
  • Lopinavir
  • Nelfinavir
  • Ritonavir
  • Saquinavir
  • Tipranavir
• Hepatitis C virus NS3/4A protease inhibitors—class stem {{not a typo|–previr}}{{rp|26}}
  • 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 {{not a typo|–trelvir}}WEB, Programme on International Nonproprietary Names (INN), Pre-stems: Suffixes used in the selection of INN - February 2023,weblink World Health Organization, February 2023,
  • Ensitrelvir
  • NirmatrelvirJOURNAL, Ahmad B, Batool M, Ain QU, Kim MS, Choi S, August 2021, Exploring the Binding Mechanism of PF-07321332 SARS-CoV-2 Protease Inhibitor through Molecular Dynamics and Binding Free Energy Simulations, International Journal of Molecular Sciences, 22, 17, 9124, 10.3390/ijms22179124, 8430524, 34502033, free,
  • Simnotrelvir

{{div col end}}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 ({{not a typo|–mastat}}) and proteasome inhibitor ({{not a typo|–zomib}}).

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 18,000WEB, HIV Surveillance --- United States, 1981--2008,weblink 8 November 2013, Prior to this the annual death rate had been increasing by approximately 20% each year.(File:AIDS diagnoses and deaths in the U.S. 1981–2008.svg|thumb|750px|center|alt=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|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){| class="wikitable"

Name >

Trade name >

Company >

Patent >

FDA approval date >| Notes

Saquinavir >

Hoffmann–La Roche >

5196438}}

December 6, 1995

The first protease inhibitor approved by the U.S. Food and Drug Administration (FDA).

Ritonavir >

AbbVie Inc.>AbbVie

{{US patent

PUBLISHER=PHARMACEUTICAL PR

EDITION=69, 426,

Indinavir >

Merck & Co. >

5413999}}

March 13, 1996

—

Nelfinavir >

Hoffmann–La Roche >

5484926}}

March 14, 1997

—

Amprenavir >

GlaxoSmithKline >

5585397}}

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 >

AbbVie Inc.>AbbVie

{{US patent

| Is only marketed as a fixed-dose combination with ritonavir (see lopinavir/ritonavir). AbbVie was part of Abbott Laboratories when patent was granted.

Atazanavir >

Bristol-Myers Squibb >

5849911}}

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>

GlaxoSmithKline >

| 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 >

Boehringer Ingelheim >

| Also known as tipranavir disodium.

Darunavir >

Janssen Pharmaceutica>Janssen Therapeutics

{{US patent

OARAC recommended treatment option for treatment-naïve and treatment-experienced adults and adolescents.GUIDELINES FOR THE USE OF ANTIRETROVIRAL AGENTS IN HIV-1-INFECTED ADULTS AND ADOLESCENTS

PUBLISHER = DEVELOPED BY THE DHHS PANEL ON ANTIRETROVIRAL GUIDELINES FOR ADULTS AND ADOLESCENTS—A WORKING GROUP OF THE OFFICE OF AIDS RESEARCH ADVISORY COUNCIL (OARAC)

DATE=JULY 14, 2016, Several ongoing Clinical trial#Phase III

trials are showing a high efficiency for the darunavir/ritonavir combination being superior to the lopinavir/ritonavir combination for first-line therapy.MADRUGA JV

JOURNAL=LANCET

ISSUE=9581

DATE=JUL 2007

DOI=10.1016/S0140-6736(07)61049-6

AUTHOR2=BERGER D

DISPLAY-AUTHORS=3

FIRST4=FREDY

FIRST5=DENES

FIRST6=KIAT

FIRST7=DORECE

FIRST8=ERIC

FIRST9=MARIE-PIERRE

Leapfrogging>leapfrogged two other approved drugs of its type, and is matching the price of a third.Liz Highleyman, Patient Advocates Commend Pricing of New PI Darunavir,weblinkDarunavir - first molecule to treat drug-resistant HIVBORMAN S >TITLE=RETAINING EFFICACY AGAINST EVASIVE HIV: DARUNAVIR ANALOG TO AIDS-VIRUS SHAPESHIFTERS: RESISTANCE MAY BE FUTILE

VOLUME=84

PAGES=9

URL=HTTP://PUBS.ACS.ORG/CEN/NEWS/84/I34/8434DRUGDESIGN.HTML, 10.1021/cen-v084n034.p009,

Other activities

Non-antiretroviral antiviral activity

A drug combination targeting SARS-CoV-2 from Pfizer, Paxlovid, was approved on December 22, 2021.WEB, FDA authorizes 1st antiviral pill for COVID --- United States, 2021, NPR,weblink 22 December 2021, It is a combination of nirmatrelvir, a protease inhibitor targeted to SARS-CoV-2's 3C-like protease, and ritonavir to inhibit nirmatrelvir's metabolism.WEB, Woodley M, 19 October 2021, What is Australia's potential new COVID treatment?,weblink 6 November 2021, The Royal Australian College of General Practitioners (RACGP), 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-protozoals for use against malaria and gastrointestinal protozoal infections:

• A combination of ritonavir and lopinavir was found to have some effectiveness against Giardia infection.JOURNAL, Dunn LA, The activity of protease inhibitors against Giardia duodenalis and metronidazole-resistant Trichomonas vaginalis, Int. J. Antimicrob. Agents, 29, 1, 98–102, 2007, 17137752, 10.1016/j.ijantimicag.2006.08.026, vanc, Andrews KT, McCarthy JS, 3, Wright, Janelle M., Skinner-Adams, Tina S., Upcroft, Peter, Upcroft, Jacqueline A.,
• The drugs saquinavir, ritonavir, and lopinavir have been found to have anti-malarial properties.JOURNAL, Andrews KT, Potencies of Human Immunodeficiency Virus Protease Inhibitors In Vitro against Plasmodium falciparum and In Vivo against Murine Malaria, Antimicrob. Agents Chemother., 50, 2, 639–48, 2006, 16436721, 10.1128/AAC.50.2.639-648.2006, 1366900, vanc, Fairlie DP, Madala PK, 3, Ray, J., Wyatt, D. M., Hilton, P. M., Melville, L. A., Beattie, L., Gardiner, D. L.,
• A cysteine protease inhibitor drug was found to cure Chagas disease in mice.JOURNAL, Doyle PS, Zhou YM, Engel JC, McKerrow JH, A Cysteine Protease Inhibitor Cures Chagas' Disease in an Immunodeficient-Mouse Model of Infection, Antimicrobial Agents and Chemotherapy, 51, 11, 3932–9, 2007, 17698625, 10.1128/AAC.00436-07, 2151429,

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).JOURNAL,weblink J.J. Gills, Nelfinavir, A Lead HIV Protease Inhibitor, Is a Broad-Spectrum, Anticancer Agent that Induces Endoplasmic Reticulum Stress, Autophagy, and Apoptosis In vitro and In vivo, Clinical Cancer Research, 13, 5183–94, 2007, 10.1158/1078-0432.CCR-07-0161, 17785575, 17, vanc, 1, Lopiccolo, J., Tsurutani, J., Shoemaker, R. H., Best, C. J.M., Abu-Asab, M. S., Borojerdi, J., Warfel, N. A., Gardner, E. R., free, JOURNAL, HIV-1 protease inhibitors nelfinavir and atazanavir induce malignant glioma death by triggering endoplasmic reticulum stress, Cancer Research, 67, 10920–8, 2007, 10.1158/0008-5472.CAN-07-0796, Pyrko, P., 18006837, Kardosh, A, Wang, W, Xiong, W, Schönthal, AH, Chen, TC, 22, free, 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.JOURNAL, 12626882, 2003, Fantry, LE, Protease inhibitor-associated diabetes mellitus: A potential cause of morbidity and mortality, 32, 3, 243–4, Journal of Acquired Immune Deficiency Syndromes, 10.1097/00126334-200303010-00001, free, This lipodystrophy is colloquially known as "Crix belly", after indinavir (Crixivan).JOURNAL, Protease inhibitors' metabolic side effects: cholesterol, triglycerides, blood sugar, and "Crix belly", AIDS Treatment News, 277, 1–4, 1997, 11364559, Capaldini, L.,

See also

• The Proteolysis Map
• Reverse-transcriptase inhibitor
• Discovery and development of NS5A inhibitors
• Discovery and development of HIV-protease inhibitors

References

{{reflist|2}}

External links

• A weblink" title="archive.today/20130116061420weblink">brief history of the development of protease inhibitors by Hoffman La Roche, Abbott, and Merck
• HIV/AIDS Treatment Guidelines US Department of Health and Human Services

{{HIVpharm}}{{RNA antivirals}}{{Enzyme inhibition}}