Protease inhibitor (pharmacology)

Class of antiviral drugs used to treat HIV/AIDS and hepatitis C

For natural protease inhibitors, see Protease inhibitor (biology).

This article needs attention from an expert in Pharmacology. The specific problem is: non-antiviral types in Template:Enzyme inhibition. WikiProject Pharmacology may be able to help recruit an expert. (January 2020)

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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[1]: 23
* Amprenavir
* Atazanavir
* Darunavir
* Fosamprenavir
* Indinavir
* Lopinavir
* Nelfinavir
* Ritonavir
* Saquinavir
* Tipranavir
* Hepatitis C virus NS3/4A protease inhibitors—class stem –previr[1]: 26
* Asunaprevir
* Boceprevir
* Grazoprevir
* Glecaprevir
* Paritaprevir
* Simeprevir
* Telaprevir
* Voxilaprevir
* 3-chymotrypsin-like protease (including, but not limited to, severe acute respiratory syndrome coronavirus 2) inhibitors—class stem –trelvir[2]
* Ensitrelvir
* Nirmatrelvir[3]
* 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).[1]

## Antiretroviral protease inhibitors

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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.[4] Most ARPIs are peptide-like molecules which resemble the substrate of the viral protease.[4]

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[5] Prior to this the annual death rate had been increasing by approximately 20% each year.

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 Name | Trade name | Company | Patent | FDA approval date | Notes

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Saquinavir | Invirase, Fortovase | Hoffmann–La Roche | U.S. patent 5,196,438 | December 6, 1995 | The first protease inhibitor approved by the U.S. Food and Drug Administration (FDA).
Ritonavir | Norvir | AbbVie | U.S. patent 5,541,206 | March 1, 1996 | AbbVie was part of Abbott Laboratories when patent was granted. As well as being a protease inhibitor in its own right, ritonavir inhibits the breakdown of other protease inhibitors. This property makes it very useful in drug combinations.[6]
Indinavir | Crixivan | Merck & Co. | U.S. patent 5,413,999 | March 13, 1996 | —
Nelfinavir | Viracept | Hoffmann–La Roche | U.S. patent 5,484,926 | March 14, 1997 | —
Amprenavir | Agenerase | GlaxoSmithKline | U.S. patent 5,585,397 | 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 | Kaletra | AbbVie | U.S. patent 5,914,332 | September 15, 2000 | Is only marketed as a fixed-dose combination with ritonavir (see lopinavir/ritonavir). AbbVie was part of Abbott Laboratories when patent was granted.
Atazanavir | Reyataz | Bristol-Myers Squibb | U.S. patent 5,849,911 | 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 | — | October 20, 2003 | 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 | Aptivus | Boehringer Ingelheim | — | June 22, 2005 | Also known as tipranavir disodium.
Darunavir | Prezista | Janssen Therapeutics | U.S. patent 6,248,775 | June 23, 2006 | As of 2016, darunavir is an OARAC recommended treatment option for treatment-naïve and treatment-experienced adults and adolescents.[7] 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.[8] Darunavir is the first drug in a long time that did not come with a price increase. It leapfrogged two other approved drugs of its type, and is matching the price of a third.[9][10][11]

## Non-antiretroviral antiviral activity

[edit]

A drug combination targeting SARS-CoV-2, Paxlovid, was approved in December 2021 to treat COVID-19.[12] 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.[13]

## Side effects

[edit]

Protease inhibitors can cause a syndrome of lipodystrophy, hyperlipidemia, diabetes mellitus type 2, and kidney stones.[14] This lipodystrophy is colloquially known as "Crix belly", after indinavir (Crixivan).[15]

## See also

[edit]

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

## References

[edit]

1. ^ a b c "The Use of Stems in the Selection of International Nonproprietary Names (INN) for Pharmaceutical Substances" (PDF). World Health Organization. Retrieved 5 November 2016.
2. ^ Programme on International Nonproprietary Names (INN) (February 2023). "Pre-stems: Suffixes used in the selection of INN - February 2023". World Health Organization.
3. ^ 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. doi:10.3390/ijms22179124. PMC 8430524. PMID 34502033.
4. ^ a b "Protease Inhibitors (HIV)", LiverTox: Clinical and Research Information on Drug-Induced Liver Injury, Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases, 2012, PMID 31644200, retrieved 2024-06-20
5. ^ "HIV Surveillance 
 United States, 1981--2008". Retrieved 8 November 2013.
6. ^ British National Formulary 69 (69 ed.). Pharmaceutical Pr. March 31, 2015. p. 426\. ISBN 9780857111562.
7. ^ "Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents" (PDF). Developed by the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents—A Working Group of the Office of AIDS Research Advisory Council (OARAC). July 14, 2016. Retrieved 5 November 2016.
8. ^ Madruga JV, Berger D, McMurchie M, et al. (Jul 2007). "Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial". Lancet. 370 (9581): 49–58\. doi:10.1016/S0140-6736(07)61049-6. PMID 17617272. S2CID 26084893.
9. ^ Liz Highleyman, Patient Advocates Commend Pricing of New PI Darunavir, http://www.hivandhepatitis.com/recent/2006/ad1/063006_a.html
10. ^ Darunavir - first molecule to treat drug-resistant HIV
11. ^ Borman S (2006). "Retaining Efficacy Against Evasive HIV: Darunavir analog to AIDS-virus shapeshifters: Resistance may be futile". Chemical & Engineering News. 84 (34): 9. doi:10.1021/cen-v084n034.p009.
12. ^ "First doses of Paxlovid, Pfizer's new COVID pill, are released to states". NPR. 23 December 2021. Retrieved 23 December 2021.
13. ^ "Paxlovid: Drug label information". DailyMed, US National Library of Medicine. 18 October 2023. Retrieved 14 June 2024.
14. ^ Fantry, LE (2003). "Protease inhibitor-associated diabetes mellitus: A potential cause of morbidity and mortality". Journal of Acquired Immune Deficiency Syndromes. 32 (3): 243–4\. doi:10.1097/00126334-200303010-00001. PMID 12626882.
15. ^ Capaldini, L. (1997). "Protease inhibitors' metabolic side effects: cholesterol, triglycerides, blood sugar, and "Crix belly"". AIDS Treatment News (277): 1–4\. PMID 11364559.

## External links

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* A 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

* v
* t
* e

Antiviral drugs: antiretroviral drugs used against HIV (primarily J05)

Capsid inhibitors|

* Lenacapavir (LEN)

Entry/fusion inhibitors
(Discovery and development)|

* gp41 (Enfuvirtide (ENF, T-20))◊
* CCR5 (Maraviroc (MVC)
* Vicriviroc†, Cenicriviroc†, Leronlimab†)
* CD4 (Ibalizumab (IBA), Semzuvolimab§)
* gp120 (Fostemsavir (FTR))

Integrase inhibitors
(Integrase strand transfer inhibitors (INSTI))|

* Bictegravir (BIC)
* Cabotegravir (CAB)
* Dolutegravir (DTG)#
* Elvitegravir (EVG)
* Raltegravir (RAL)#
* BI 224436†
* MK-2048†

Maturation inhibitors|

* Bevirimat†
* BMS-955176§
* Fipravirimat§

Protease Inhibitors (PI)
(Discovery and development)|

| 1st generation|

* Amprenavir (APV)‡
* Fosamprenavir (FPV)
* Indinavir (IDV)◊
* Lopinavir (LPV)
* Nelfinavir (NFV)◊
* Ritonavir (RTV)#
* Saquinavir (SQV)◊

|

2nd generation|

* Atazanavir (ATV)°#
* Darunavir (DRV)°#
* Tipranavir (TPV)◊
* TMC-310911§

Reverse-transcriptase
inhibitors (RTIs)|

| Nucleoside and
nucleotide (NRTI)|

* Nucleoside analogues/NRTIs: Abacavir (ABC)#
* Didanosine (ddI)◊
* Emtricitabine (FTC)
* Lamivudine (3TC)#
* Stavudine (d4T)◊
* Zalcitabine (ddC)‡
* Zidovudine (AZT, ZDV)#
* Amdoxovir†
* Apricitabine†
* Censavudine†
* Elvucitabine†
* Islatravir (EFdA, ISL)§
* Racivir†
* Stampidine†

* Nucleotide analogues/NtRTIs: Tenofovir disoproxil (TDF)#
* Tenofovir alafenamide (TAF)

|

Non-nucleoside (NNRTI)
(Discovery and development)|

| 1st generation|

* Efavirenz (EFV)#
* Nevirapine (NVP)#
* Delavirdine (DLV)‡

|

2nd generation|

* diarylpyrimidines
* Dapivirine (DPV)
* Etravirine (ETR)
* Rilpivirine (RPV)
* Doravirine (DOR)
* Elsulfavirine (ESV)

Combined formulations|

* Abacavir/lamivudine#
* Abacavir/dolutegravir/lamivudine°
* Abacavir/lamivudine/zidovudine
* Atazanavir/cobicistat
* Bictegravir/emtricitabine/tenofovir alafenamide°
* Cabotegravir/rilpivirine
* Darunavir/cobicistat
* Darunavir/cobicistat/emtricitabine/tenofovir alafenamide°
* Dolutegravir/emtricitabine/tenofovir alafenamide
* Dolutegravir/lamivudine°
* Dolutegravir/lamivudine/tenofovir alafenamide°
* Dolutegravir/lamivudine/tenofovir disoproxil°#
* Dolutegravir/rilpivirine
* Doravirine/lamivudine/tenofovir disoproxil
* Efavirenz/emtricitabine/tenofovir disoproxil#
* Efavirenz/lamivudine/tenofovir disoproxil#
* Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide
* Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil
* Emtricitabine/tenofovir alafenamide
* Emtricitabine/rilpivirine/tenofovir alafenamide
* Emtricitabine/rilpivirine/tenofovir disoproxil
* Emtricitabine/tenofovir disoproxil#
* Lamivudine/nevirapine/stavudine
* Lamivudine/nevirapine/zidovudine
* Lamivudine/raltegravir
* Lamivudine/tenofovir disoproxil#
* Lamivudine/zidovudine#
* Lopinavir/ritonavir#

Pharmacokinetic boosters|

* Cobicistat (c)
* Ritonavir (r)#

Experimental agents|

| Uncoating inhibitors|

* TRIM5alpha (gene)

|

Transcription inhibitors|

* Tat antagonists

Translation inhibitors|

* Trichosanthin

BNAbs|

* Elipovimab

Other|

* Abzyme
* BIT225†
* Calanolide A
* Ceragenin
* Cyanovirin-N
* Diarylpyrimidines
* Epigallocatechin gallate (EGCG)
* Foscarnet
* Fosdevirine†
* Griffithsin
* Hydroxycarbamide
* KP-1461†
* Miltefosine
* North-methanocarbathymidine
* Portmanteau inhibitors
* Scytovirin
* Seliciclib†
* Synergistic enhancers
* Tre recombinase
* Zinc finger protein transcription factor

Failed agents|

* Aplaviroc
* Atevirdine
* Brecanavir
* Capravirine
* Dexelvucitabine
* Droxinavir
* Lasinavir
* Emivirine
* Lersivirine
* Lodenosine
* Loviride
* Mozenavir
* Palinavir
* Telinavir

* #WHO-EM
* ‡Withdrawn from market
* Clinical trials:
* †Phase III
* §Never to phase III

°DHHS recommended initial regimen options. ◊Formerly or rarely used agent.

* v
* t
* e

RNA virus antivirals (primarily J05, also S01AD and D06BB)

Hepatitis C|

| NS3/4A protease inhibitors (–previr)|

* Asunaprevir
* Boceprevir‡
* Ciluprevir§
* Danoprevir†
* Faldaprevir‡
* Glecaprevir
* Grazoprevir
* Narlaprevir
* Paritaprevir
* Simeprevir
* Sovaprevir†
* Telaprevir‡
* Vaniprevir
* Vedroprevir§
* Voxilaprevir

|

NS5A inhibitors (–asvir)|

* Coblopasvir
* Daclatasvir#
* Elbasvir
* Ledipasvir
* Odalasvir†
* Ombitasvir
* Pibrentasvir
* Ravidasvir†
* Ruzasvir†
* Samatasvir†
* Velpatasvir

NS5B RNA polymerase inhibitors (–buvir)|

* Beclabuvir†
* Bemnifosbuvir†
* Dasabuvir#
* Deleobuvir§
* Filibuvir§
* GS-6620§
* IDX-184§
* Setrobuvir§
* Sofosbuvir#
* Tegobuvir§
* TMC-647055§
* Radalbuvir†
* Uprifosbuvir†

Combination drugs|

* Elbasvir/grazoprevir
* Glecaprevir/pibrentasvir
* Ledipasvir/sofosbuvir#
* Ombitasvir/paritaprevir/ritonavir#
* Sofosbuvir/daclatasvir
* Sofosbuvir/velpatasvir#
* Sofosbuvir/velpatasvir/voxilaprevir

Hepatitis D|

* Bulevirtide

Picornavirus|

* viral entry: Pleconaril†

Anti-influenza agents|

* Baloxavir marboxil
* Pimodivir†
* Umifenovir

* adamantane derivatives/M2 inhibitors (Adapromine
* Amantadine
* Rimantadine)

* neuraminidase inhibitors/release phase (Oseltamivir#
* Zanamivir
* Peramivir, Laninamivir†)

Multiple/general|

| Interferon|

* Interferon alfa 2b
* Peginterferon alfa-2a#
* Peginterferon alfa-2b#

|

3CL protease inhibitors (–trelvir)|

* Atilotrelvir
* Ensitrelvir†
* Ibuzatrelvir
* Leritrelvir
* Lufotrelvir
* Nirmatrelvir† (+ritonavir)†
* Rupintrivir
* Simnotrelvir (+ritonavir†)

RNA pol inhibitors|

* CMX521§
* Deuremidevir†
* Favipiravir
* Galidesivir†
* GS-441524§
* Remdesivir
* MK-608§
* Mericitabine†
* Molnupiravir
* NITD008§
* Ribavirin#
* Taribavirin†
* Triazavirin
* Valopicitabine†

Multiple/Unknown/Other|

* EICAR§
* Merimepodib§
* Moroxydine
* Presatovir†

* #WHO-EM
* ‡Withdrawn from market
* Clinical trials:
* †Phase III
* §Never to phase III

* v
* t
* e

Pharmacology: enzyme inhibition

Class|

* Competitive inhibition
* Uncompetitive inhibition
* Non-competitive inhibition
* Suicide inhibition
* Mixed inhibition

Substrate|

| Oxidoreductase (EC 1)|

* 1.1 Aldose reductase
* HMG-CoA reductase

* 1.3 5α-Reductase

* 1.4 Monoamine oxidase

* 1.5 Dihydrofolate reductase

* 1.13 Lipoxygenase

* 1.14 Aromatase
* COX-2

* 1.17 Xanthine oxidase
* Ribonucleotide reductase

|

Transferase (EC 2)|

* 2.1 COMT
* Thymidylate synthase

* 2.4 PARP

* 2.5 Dihydropteroate synthetase
* Farnesyltransferase

* 2.6 GABA transaminase

* 2.7 Nucleotidyltransferase
* Integrase
* Reverse transcriptase
* Protein kinase
* Tyrosine kinase
* Janus kinase

Hydrolase (EC 3)|

* 3.1 Phosphodiesterase
* Acetylcholinesterase
* Ribonuclease

* 3.2 Polygalacturonase
* Neuraminidase
* Alpha-glucosidase

* 3.4 Protease: Exopeptidase
* DPP-4
* ACE
* Endopeptidase
* Trypsin
* Renin
* Mixed
* Enkephalinase
* Matrix metalloproteinase
* Oxytocinase

* 3.5 Histone deacetylase
* Beta-lactamase

Lyase (EC 4)|

* 4.1 Dopa decarboxylase

* 4.2 Carbonic anhydrase

Miscellaneous|

* Steroidogenesis inhibitor

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