Protease inhibitor (pharmacology)

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

Protease inhibitors (PIs) are a class of antiviral drugs that are widely used to treat HIV/AIDS and hepatitis caused by hepatitis C virus. Protease inhibitors prevent viral replication 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 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.


Protease inhibitors were the second class of antiretroviral drugs developed. The first members of this class, saquinavir (Hoffman-La Roche) and ritonavir (Abbott), 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 [2] 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 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 Agouron Pharmaceuticals 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 1,200 mg, 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 Production was discontinued by the manufacturer December 31, 2004, as it has been superseded by fosamprenavir.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 U.S. Patent 5,914,332 Is only marketed as a combination, with ritonavir.
Atazanavir Reyataz Bristol-Myers Squibb U.S. Patent 5,849,911 The FDA approved it on 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 - Is a prodrug 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 U.S. Patent 6,248,775 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 adolescents.[3] 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.[4] 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 third.[5][6][7]

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.[8]
  • The drugs saquinavir, ritonavir, and lopinavir have been found to have anti-malarial properties.[9]
  • A cysteine protease inhibitor drug was found to cure Chagas disease in mice.[10]

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).[11][12] 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.[12]

Inhibitors of the proteasome, such as Velcade/Bortezomib are now front-line drugs for the treatment of various cancers, notably Multiple Myeloma.

Tanomastat is one of the matrix metalloproteinase inhibitors that can be used to treat cancer.

Side effects[edit]

Protease inhibitors can cause a syndrome of lipodystrophy, hyperlipidaemia, diabetes mellitus type 2, and kidney stones.[13] This lipodystrophy is colloquially known as "Crix belly", after Crixivan.[14]

See also[edit]


  1. ^ Rang, H. P., Dale, M. M., Ritter, J. M., & Flower, R. J. (2007). Rang and Dale's Pharmacology (6th Edition ed.). Philadelphia: Churchill Livingstone Elsevier.
  2. ^ "HIV Surveillance --- United States, 1981--2008". Retrieved 8 November 2013. 
  3. ^ 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.
  4. ^ 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. 
  5. ^ Liz Highleyman, Patient Advocates Commend Pricing of New PI Darunavir,
  6. ^ Darunavir - first molecule to treat drug-resistant HIV
  7. ^ 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. 
  8. ^ 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. 
  9. ^ 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 1366900free to read. PMID 16436721. 
  10. ^ 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 2151429free to read. PMID 17698625. 
  11. ^ 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. 
  12. ^ a b Pyrko, 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. 
  13. ^ Fantry, LE (2003). "Protease inhibitor-associated diabetes mellitus: A potential cause of morbidity and mortality". Journal of acquired immune deficiency syndromes (1999). 32 (3): 243–4. doi:10.1097/00126334-200303010-00001. PMID 12626882. 
  14. ^ "Protease inhibitors' metabolic side effects: cholesterol, triglycerides, blood sugar, and "Crix belly"". AIDS Treatment News (277): 1–4. 1997. PMID 11364559. 

External links[edit]

  • A brief history of the development of protease inhibitors by Hoffman La Roche, Abbott, and Merck