Protease inhibitor (pharmacology)

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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.

Contents

Protease inhibitors that have been developed and are currently used in clinical practice include:

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

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 AIDS diagnoses and deaths in the U.S. 1981-2008.svg
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
NameTrade nameCompanyPatentFDA approval dateNotes
Saquinavir Invirase, Fortovase Hoffmann–La Roche U.S. patent 5,196,438 December 6, 1995The first protease inhibitor approved by the U.S. Food and Drug Administration (FDA).
Ritonavir Norvir AbbVie U.S. patent 5,541,206 March 1, 1996AbbVie 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, 1999The 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, 2000Is 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, 2003Atazanavir 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, 2003A 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, 2005Also known as tipranavir disodium.
Darunavir Prezista Janssen Therapeutics U.S. patent 6,248,775 June 23, 2006As 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

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

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

Related Research Articles

The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multiple drugs that act on different viral targets is known as highly active antiretroviral therapy (HAART). HAART decreases the patient's total burden of HIV, maintains function of the immune system, and prevents opportunistic infections that often lead to death. HAART also prevents the transmission of HIV between serodiscordant same-sex and opposite-sex partners so long as the HIV-positive partner maintains an undetectable viral load.

<span class="mw-page-title-main">Atazanavir</span> Chemical compound

Atazanavir, sold under the brand name Reyataz among others, is an antiretroviral medication used to treat HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needlestick injury or other potential exposure. It is taken by mouth.

<span class="mw-page-title-main">Ritonavir</span> Antiretroviral medication

Ritonavir, sold under the brand name Norvir, is an antiretroviral medication used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). Ritonavir is a protease inhibitor, though it now mainly serves to boost the potency of other protease inhibitors. It may also be used in combination with other medications to treat hepatitis C and COVID-19. It is taken by mouth. Tablets of ritonavir are not bioequivalent to capsules, as the tablets may result in higher peak plasma concentrations.

<span class="mw-page-title-main">Saquinavir</span> Chemical compound

Saquinavir, sold under the brand name Invirase among others, is an antiretroviral medication used together with other medications to treat or prevent HIV/AIDS. Typically it is used with ritonavir or lopinavir/ritonavir to increase its effect. It is taken by mouth.

<span class="mw-page-title-main">Tipranavir</span> Chemical compound

Tipranavir (TPV), or tipranavir disodium, is a nonpeptidic protease inhibitor (PI) manufactured by Boehringer Ingelheim under the trade name AptivusAP-tiv-əs. It is administered with ritonavir in combination therapy to treat HIV infection.

<span class="mw-page-title-main">Indinavir</span> Chemical compound

Indinavir is a protease inhibitor used as a component of highly active antiretroviral therapy to treat HIV/AIDS. It is soluble white powder administered orally in combination with other antiviral drugs. The drug prevents protease from functioning normally. Consequently, HIV viruses cannot reproduce, causing a decrease in the viral load. Commercially sold indinavir is indinavir anhydrous, which is indinavir with an additional amine in the hydroxyethylene backbone. This enhances its solubility and oral bioavailability, making it easier for users to intake. It was synthetically produced for the purpose of inhibiting the protease in the HIV virus.

<span class="mw-page-title-main">Fosamprenavir</span> Chemical compound

Fosamprenavir (FPV), sold under the brand names Lexiva and Telzir, is a medication used to treat HIV/AIDS. It is a prodrug of the protease inhibitor and antiretroviral drug amprenavir. It is marketed by ViiV Healthcare as the calcium salt.

<span class="mw-page-title-main">Lopinavir</span> Chemical compound

Lopinavir is an antiretroviral of the protease inhibitor class. It is used against HIV infections as a fixed-dose combination with another protease inhibitor, ritonavir (lopinavir/ritonavir).

<span class="mw-page-title-main">Darunavir</span> Antiretroviral medication

Darunavir (DRV), sold under the brand name Prezista among others, is an antiretroviral medication used to treat and prevent HIV/AIDS. It is generally recommended for use with other antiretrovirals. It is often used with low doses of ritonavir or cobicistat to increase darunavir levels. It may be used for prevention after a needlestick injury or other potential exposure. It is taken by mouth once to twice a day.

<span class="mw-page-title-main">HIV-1 protease</span> Enzyme involved with peptide bond hydrolysis in retroviruses

HIV-1 protease or PR is a retroviral aspartyl protease (retropepsin), an enzyme involved with peptide bond hydrolysis in retroviruses, that is essential for the life-cycle of HIV, the retrovirus that causes AIDS. HIV-1 PR cleaves newly synthesized polyproteins at nine cleavage sites to create the mature protein components of an HIV virion, the infectious form of a virus outside of the host cell. Without effective HIV-1 PR, HIV virions remain uninfectious.

<span class="mw-page-title-main">Elvitegravir</span> Chemical compound

Elvitegravir (EVG) is an integrase inhibitor used to treat HIV infection. It was developed by the pharmaceutical company Gilead Sciences, which licensed EVG from Japan Tobacco in March 2008. The drug gained approval by the U.S. Food and Drug Administration on August 27, 2012, for use in adult patients starting HIV treatment for the first time as part of the fixed dose combination known as Stribild. On September 24, 2014, the FDA approved Elvitegravir as a single pill formulation under the trade name Vitekta. On November 5, 2015, the FDA approved the drug for use in patients affected with HIV-1 as a part of a second fixed dose combination pill known as Genvoya.

Many major physiological processes depend on regulation of proteolytic enzyme activity and there can be dramatic consequences when equilibrium between an enzyme and its substrates is disturbed. In this prospective, the discovery of small-molecule ligands, like protease inhibitors, that can modulate catalytic activities has an enormous therapeutic effect. Hence, inhibition of the HIV protease is one of the most important approaches for the therapeutic intervention in HIV infection and their development is regarded as major success of structure-based drug design. They are highly effective against HIV and have, since the 1990s, been a key component of anti-retroviral therapies for HIV/AIDS.

<span class="mw-page-title-main">Cobicistat</span> Chemical compound

Cobicistat, sold under the brand name Tybost, is a medication for use in the treatment of human immunodeficiency virus infection (HIV/AIDS). Its major mechanism of action is through the inhibition of human CYP3A proteins.

<span class="mw-page-title-main">Lopinavir/ritonavir</span> Combination medication for HIV/AIDS

Lopinavir/ritonavir (LPV/r), sold under the brand name Kaletra among others, is a fixed-dose combination antiretroviral medication for the treatment and prevention of HIV/AIDS. It combines lopinavir with a low dose of ritonavir. It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needlestick injury or other potential exposure. It is taken by mouth as a tablet, capsule, or solution.

<span class="mw-page-title-main">3C-like protease</span> Class of enzymes

The 3C-like protease (3CLpro) or main protease (Mpro), formally known as C30 endopeptidase or 3-chymotrypsin-like protease, is the main protease found in coronaviruses. It cleaves the coronavirus polyprotein at eleven conserved sites. It is a cysteine protease and a member of the PA clan of proteases. It has a cysteine-histidine catalytic dyad at its active site and cleaves a Gln–(Ser/Ala/Gly) peptide bond.

<span class="mw-page-title-main">Grazoprevir</span> Drug approved for the treatment of hepatitis C

Grazoprevir is a drug approved for the treatment of hepatitis C. It was developed by Merck and completed Phase III trials, used in combination with the NS5A replication complex inhibitor elbasvir under the trade name Zepatier, either with or without ribavirin.

<span class="mw-page-title-main">Nirmatrelvir</span> COVID-19 antiviral medication

Nirmatrelvir is an antiviral medication developed by Pfizer which acts as an orally active 3C-like protease inhibitor. It is part of a nirmatrelvir/ritonavir combination used to treat COVID-19 and sold under the brand name Paxlovid.

<span class="mw-page-title-main">Charles Flexner</span> American physician and pharmaceutical scientist

Charles Williams Flexner is an American physician, clinical pharmaceutical scientist, academic, author and researcher. He is a Professor of Medicine at the Johns Hopkins University School of Medicine.

In the management of HIV/AIDS, HIV capsid inhibitors are antiretroviral medicines that target the capsid shell of the virus. Most current antiretroviral drugs used to treat HIV do not directly target the viral capsid. These have also been termed "Capsid-targeting Antivirals", "Capsid Effectors", and "Capsid Assembly Modulators (CAMs)". Because of this, drugs that specifically inhibit the HIV capsid are being developed in order to reduce the replication of HIV, and treat infections that have become resistant to current antiretroviral therapies.

<span class="mw-page-title-main">Nirmatrelvir/ritonavir</span> Antiviral combination medication

Nirmatrelvir/ritonavir, sold under the brand name Paxlovid, is a co-packaged medication used as a treatment for COVID‑19. It contains the antiviral medications nirmatrelvir and ritonavir and was developed by Pfizer. Nirmatrelvir inhibits SARS-CoV-2 main protease, while ritonavir is a strong CYP3A inhibitor, slowing down nirmatrelvir metabolism and therefore boosting its effect. It is taken by mouth.

References

  1. 1 2 3 "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. 1 2 "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.
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