Protease inhibitors


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Protease inhibitors



Protein synthesis inhibitors: Aminoglycosides

Antimetabolites: Sulfonamides and trimethoprim

Antituberculosis medications

Miscellaneous cell wall synthesis inhibitors

Protein synthesis inhibitors: Tetracyclines

Cell wall synthesis inhibitors: Penicillins

Miscellaneous protein synthesis inhibitors

Cell wall synthesis inhibitors: Cephalosporins

DNA synthesis inhibitors: Metronidazole

DNA synthesis inhibitors: Fluoroquinolones

Mechanisms of antibiotic resistance


Integrase and entry inhibitors

Nucleoside reverse transcriptase inhibitors (NRTIs)

Protease inhibitors

Hepatitis medications

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Neuraminidase inhibitors

Herpesvirus medications




Miscellaneous antifungal medications


Anthelmintic medications


Anti-mite and louse medications


Protease inhibitors


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Protease inhibitors

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Atazanavir p. 198, 200


Content Reviewers

Yifan Xiao, MD


Filip Vasiljević, MD

Ursula Florjanczyk, MScBMC

Marisa Pedron

Evan Debevec-McKenney

Protease inhibitors are an important part of HAART, or highly active antiretroviral therapy, which is the combination of medications used in the treatment of AIDS.

AIDS is caused by an RNA containing retrovirus called human immunodeficiency virus, or HIV.

Protease inhibitors, or PIs, work by inhibiting the enzyme HIV-1 protease, which prevents the formation of new viruses and further infection of the host’s cells.

HIV is a single-stranded, positive-sense, enveloped RNA retrovirus that targets cells in the immune system that have molecules called CD4 on their membranes.

These include macrophages, dendritic cells, and especially CD4+ T-helper cells.

HIV attaches to the CD4 molecule via a protein called gp120 found on its envelope.

Now, inside its envelope, HIV contains a nucleocapsid which is a capsule containing a single-stranded RNA and some viral enzymes, like reverse transcriptase, integrase, and aspartate protease, also known as a mature HIV-1 protease.

As HIV binds to the receptors, the viral envelope fuses with the cell membrane of the immune cell, releasing the contents of the nucleocapsid into the helpless host cell’s cytoplasm.

Once it’s inside the CD4+ cell, reverse transcriptase gets to work immediately.

It uses the single-stranded viral RNA as a template and uses the nucleotides present in the cytoplasm of the CD4+ cell to transcribe a complementary double-stranded “proviral” DNA.

This proviral DNA enters the T-helper cell’s nucleus and pops itself into the cell’s DNA, ready to be transcribed into messenger RNA (mRNA).

These mRNA travel to the ribosomes which translate this into long Gag-Pol polyproteins, which are a bunch of viral proteins joined together.

Now, human cells don’t come with the equipment to process these long polyprotein chains, but one of the enzymes that HIV releases into the cell is a protease called aspartate protease, or HIV-1 protease.


Protease inhibitors (PIs) are a class of antiviral drugs that are widely used to manage HIV/AIDS. Protease inhibitors prevent viral replication by selectively binding the enzyme HIV-1 protease, and prevent the formation of new viruses and further infection of the host's cells. Common medications in this class include atazanavir, darunavir, indinavir, lopinavir, tipranavir, and ritonavir. Common side effects of protease inhibitors include gastrointestinal problems such as diarrhea, nausea, and vomiting; and metabolic disorders such as hyperglycemia, insulin resistance, and hyperlipidemia.


  1. "Katzung & Trevor's Pharmacology Examination and Board Review,12th Edition" McGraw-Hill Education / Medical (2018)
  2. "Rang and Dale's Pharmacology" Elsevier (2019)
  3. "Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th Edition" McGraw-Hill Education / Medical (2017)
  4. "HIV-1 Antiretroviral Drug Therapy" Cold Spring Harbor Perspectives in Medicine (2012)
  5. "Novel Central Nervous System (CNS)-Targeting Protease Inhibitors for Drug-Resistant HIV Infection and HIV-Associated CNS Complications" Antimicrobial Agents and Chemotherapy (2019)
  6. "Three HIV Drugs, Atazanavir, Ritonavir, and Tenofovir, Coformulated in Drug-Combination Nanoparticles Exhibit Long-Acting and Lymphocyte-Targeting Properties in Nonhuman Primates" Journal of Pharmaceutical Sciences (2018)

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