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)
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.
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[4] 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
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.[5]
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 Production was discontinued by the manufacturer December 31, 2004, as it has been superseded by fosamprenavir.
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.
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.
As of 2016, darunavir is an OARAC recommended treatment option for treatment-naïve and treatment-experienced adults and adolescents.[6] 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.[7] 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.[8][9][10]
Other activitiesedit
Non-antiretroviral antiviral activityedit
A drug combination targeting SARS-CoV-2 from Pfizer, Paxlovid, was approved on December 22, 2021.[11] 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.[12]
Protease inhibitors also are used to treat Hepatitis C.
Antiprotozoal activityedit
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.[13]
The drugs saquinavir, ritonavir, and lopinavir have been found to have anti-malarial properties.[14]
A cysteine protease inhibitor drug was found to cure Chagas disease in mice.[15]
Anticancer activityedit
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).[16][17] 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.[17]
^ abc"The Use of Stems in the Selection of International Nonproprietary Names (INN) for Pharmaceutical Substances" (PDF). World Health Organization. Retrieved 5 November 2016.
^Programme on International Nonproprietary Names (INN) (February 2023). "Pre-stems: Suffixes used in the selection of INN - February 2023". World Health Organization.
^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. PMC8430524. PMID 34502033.
^"HIV Surveillance --- United States, 1981--2008". Retrieved 8 November 2013.
^British National Formulary 69 (69 ed.). Pharmaceutical Pr. March 31, 2015. p. 426. ISBN9780857111562.
^"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.
^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.
^Darunavir - first molecule to treat drug-resistant HIV
^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.
^"FDA authorizes 1st antiviral pill for COVID --- United States, 2021". NPR. Retrieved 22 December 2021.
^Woodley M (19 October 2021). "What is Australia's potential new COVID treatment?". The Royal Australian College of General Practitioners (RACGP). Retrieved 6 November 2021.
^Dunn LA, Andrews KT, McCarthy JS, et al. (2007). "The activity of protease inhibitors against Giardia duodenalis and metronidazole-resistant Trichomonas vaginalis". Int. J. Antimicrob. Agents. 29 (1): 98–102. doi:10.1016/j.ijantimicag.2006.08.026. PMID 17137752.
^Andrews KT, Fairlie DP, Madala PK, et al. (2006). "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. doi:10.1128/AAC.50.2.639-648.2006. PMC1366900. PMID 16436721.
^Doyle PS, Zhou YM, Engel JC, McKerrow JH (2007). "A Cysteine Protease Inhibitor Cures Chagas' Disease in an Immunodeficient-Mouse Model of Infection". Antimicrobial Agents and Chemotherapy. 51 (11): 3932–9. doi:10.1128/AAC.00436-07. PMC2151429. PMID 17698625.
^J.J. Gills, et al. (2007). "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 (17): 5183–94. doi:10.1158/1078-0432.CCR-07-0161. PMID 17785575.
^ abPyrko, P.; Kardosh, A; Wang, W; Xiong, W; Schönthal, AH; Chen, TC (2007). "HIV-1 protease inhibitors nelfinavir and atazanavir induce malignant glioma death by triggering endoplasmic reticulum stress". Cancer Research. 67 (22): 10920–8. doi:10.1158/0008-5472.CAN-07-0796. PMID 18006837.
^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.
^Capaldini, L. (1997). "Protease inhibitors' metabolic side effects: cholesterol, triglycerides, blood sugar, and "Crix belly"". AIDS Treatment News (277): 1–4. PMID 11364559.
External linksedit
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
February 15, 2024
protease, inhibitor, pharmacology, natural, protease, inhibitors, protease, inhibitor, biology, this, article, needs, attention, from, expert, pharmacology, specific, problem, antiviral, types, template, enzyme, inhibition, wikiproject, pharmacology, able, hel. 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 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 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 Contents 1 Antiretrovirals 2 Other activities 2 1 Non antiretroviral antiviral activity 2 2 Antiprotozoal activity 2 3 Anticancer activity 3 Side effects 4 See also 5 References 6 External linksAntiretrovirals editProtease 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 4 Prior to this the annual death rate had been increasing by approximately 20 each year nbsp 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 inhibitorsName Trade name Company Patent FDA approval date NotesSaquinavir 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 5 Indinavir Crixivan Merck amp 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 naive and treatment experienced adults and adolescents 6 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 7 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 8 9 10 Other activities editNon antiretroviral antiviral activity edit A drug combination targeting SARS CoV 2 from Pfizer Paxlovid was approved on December 22 2021 11 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 12 Protease inhibitors also are used to treat Hepatitis C Antiprotozoal activity edit 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 13 The drugs saquinavir ritonavir and lopinavir have been found to have anti malarial properties 14 A cysteine protease inhibitor drug was found to cure Chagas disease in mice 15 Anticancer activity edit 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 16 17 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 17 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 editProtease inhibitors can cause a syndrome of lipodystrophy hyperlipidemia diabetes mellitus type 2 and kidney stones 18 This lipodystrophy is colloquially known as Crix belly after indinavir Crixivan 19 See also editThe Proteolysis Map Reverse transcriptase inhibitor Discovery and development of NS5A inhibitors Discovery and development of HIV protease inhibitorsReferences edit 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 Programme on International Nonproprietary Names INN February 2023 Pre stems Suffixes used in the selection of INN February 2023 World Health Organization 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 HIV Surveillance United States 1981 2008 Retrieved 8 November 2013 British National Formulary 69 69 ed Pharmaceutical Pr March 31 2015 p 426 ISBN 9780857111562 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 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 Liz Highleyman Patient Advocates Commend Pricing of New PI Darunavir http www hivandhepatitis com recent 2006 ad1 063006 a html Darunavir first molecule to treat drug resistant HIV Borman S 2006 Retaining Efficacy Against Evasive HIV Darunavir analog to AIDS virus shapeshifters Resistance may be futile Chemical amp Engineering News 84 34 9 doi 10 1021 cen v084n034 p009 FDA authorizes 1st antiviral pill for COVID United States 2021 NPR Retrieved 22 December 2021 Woodley M 19 October 2021 What is Australia s potential new COVID treatment The Royal Australian College of General Practitioners RACGP Retrieved 6 November 2021 Dunn LA Andrews KT McCarthy JS et al 2007 The activity of protease inhibitors against Giardia duodenalis and metronidazole resistant Trichomonas vaginalis Int J Antimicrob Agents 29 1 98 102 doi 10 1016 j ijantimicag 2006 08 026 PMID 17137752 Andrews KT Fairlie DP Madala PK et al 2006 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 doi 10 1128 AAC 50 2 639 648 2006 PMC 1366900 PMID 16436721 Doyle PS Zhou YM Engel JC McKerrow JH 2007 A Cysteine Protease Inhibitor Cures Chagas Disease in an Immunodeficient Mouse Model of Infection Antimicrobial Agents and Chemotherapy 51 11 3932 9 doi 10 1128 AAC 00436 07 PMC 2151429 PMID 17698625 J J Gills et al 2007 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 17 5183 94 doi 10 1158 1078 0432 CCR 07 0161 PMID 17785575 a b Pyrko P Kardosh A Wang W Xiong W Schonthal AH Chen TC 2007 HIV 1 protease inhibitors nelfinavir and atazanavir induce malignant glioma death by triggering endoplasmic reticulum stress Cancer Research 67 22 10920 8 doi 10 1158 0008 5472 CAN 07 0796 PMID 18006837 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 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 editA 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 Retrieved from https en wikipedia org w index php title Protease inhibitor pharmacology amp oldid 1191537766, wikipedia, wiki, book, books, library,
