Protease_inhibitor_(pharmacology)

Protease inhibitors (PIs) are a class of medications used to treat or prevent infection by viruses, including HIV and Hepatitis C. PIs prevents viral replication by inhibiting the activity of HIV-1 protease, an enzyme used by the viruses to cleave nascent proteins for final assembly of new virons.

Protease inhibitors have been developed or are presently undergoing testing for treating various viruses:

Given the specificity of the target of these drugs there is the risk, as in 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.

Antiretrovirals

Protease inhibitors were the second class of antiretroviral drugs developed. In all cases, patents remain in force until 2010 or beyond.

Name	Trade name	Company	Patent	Notes
Saquinavir	Fortovase, Invirase	Hoffmann–La Roche	U.S. Patent 5,196,438	It was the first protease inhibitor approved by the FDA (December 6, 1995).
Ritonavir	Norvir	Abbott Laboratories	U.S. Patent 5,541,206	-
Indinavir	Crixivan	Merck & Co.	U.S. Patent 5,413,999	-
Nelfinavir	Viracept	Japan Tobacco	U.S. Patent 5,484,926	-
Amprenavir	Agenerase	GlaxoSmithKline	U.S. Patent 5,585,397	The FDA approved it April 15, 1999, making it 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 1,200mg, delivered in eight very large gel capsules. Production was discontinued by the manufacturer December 31, 2004, as it has been superseded by fosamprenavir.
Lopinavir	Kaletra	Abbott	-	Is only marketed as a combination, with ritonavir.
Atazanavir	Reyataz	-	-	-
Fosamprenavir	Lexiva	GlaxoSmithKline	-	Is a pro-drug of amprenavir. The FDA approved it October 20, 2003. 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	-	Also known as tipranavir disodium
Darunavir	Prezista	Tibotec	-	It was approved by the Food and Drug Administration (FDA) on June 23, 2006. Prezista is an OARAC recommended treatment option for treatment-naïve and treatment-experienced adults and adolescents². Several ongoing phase III trials are showing a high efficiency for the PREZISTA/rtv combination being superior to the lopinavir/rtv combination for first-line therapy.³ Darunavir is the first drug in a long time that didn't come with a price increase. It leapfrogged two other approved drugs of its type, and is matching the price of a third⁴.⁵⁶

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:

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).¹⁰¹¹ 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.¹¹

References

^ FDA Grants Fast Track Designation To Oral HCV Protease Inhibitor SCH 503034 [1]
^ Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, November 3, 2008, Developed by the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents – A Working Group of the Office of AIDS Research Advisory Council (OARAC). full guidelines.
^ 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.
^ 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, http://www.news-medical.net/?id=19211
^ Borman S (2006). "Retaining Efficacy Against Evasive HIV: Darunavir analog to AIDS-virus shapeshifters: Resistance may be futile". Chemical & Engineering News 84 (34): 9, http://pubs.acs.org/cen/news/84/i34/8434drugdesign.html.
^ 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. PMID 16436721.
^ Doyle PS, Zhou YM, Engel JC, McKerrow JH (2007). "A Cysteine Protease Inhibitor Cures Chagas' Disease in an, Immunodeficient Murine Model of Infection". Antimicrobial Agents and Chemotherapy 51: 3932. doi:10.1128/AAC.00436-07. 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: 5183–94. doi:10.1158/1078-0432.CCR-07-0161. PMID 17785575, http://clincancerres.aacrjournals.org/cgi/content/abstract/13/17/5183.
^ ^a ^b Pyrko, P. (2007). "HIV-1 protease inhibitors nelfinavir and atazanavir induce malignant glioma death by triggering endoplasmic reticulum stress". Cancer Research 67: 10920–8. doi:10.1158/0008-5472.CAN-07-0796. PMID 18006837.