Protease inhibitors

crop_square Key points

  • check_circle Antiretroviral PIs inhibit the key HIV enzyme aspartic protease
  • check_circle Anti-HCV PIs are direct acting antivirals (DAA) targeting non-structural protein 3-4A (NS3-4A)
  • check_circle PIs undergo extensive hepatic metabolization
  • check_circle Ritonavir and cobicistat may be given as pharmacokinetic boosters with some PIs

crop_square Background and biochemistry

Antiretroviral protease inhibitors (PIs) were developed in the 1980es and 1990, an era of extensive research on HIV drugs. Most of PIs are peptidomimetics, meaning they mimic naturally occurring proteins/peptides. Saquinavir was the first drug of this class to be approved for clinical use in 1995 and more antiretroviral PIs became available over the following years. This revolutionised the treatment of HIV/AIDS, turning what used to be a death sentence into a manageable, chronic disease. Antiretroviral PIs were primarily developed for the treatment of HIV-1 infections, but many are effective against HIV-2 as well. The recent discovery of direct acting antivirals (DAAs) active against hepatitis C virus (HCV) led to another therapeutical breakthrough. Chronic HCV is now curable for most patients with access to adequate healthcare. PIs are one of three subgroups of DAAs. The World Health Organisation (WHO) is targeting the year 2030 to eliminate chronic HCV as a public health threat. Paxlovid is a combination of nirmatrelvir/ritonavir which was recently approved for the treatment of COVID-19.

crop_square Mechanism of action

Antiretroviral PIs inhibit an HIV enzyme, aspartic protease, by binding to its active site. This enzyme plays an essential role in the life cycle of HIV. After integration of the of transcribed retroviral DNA into the host cell’s genome, HIV mRNA is generated, which is then translated into HIV protein precursors (polypeptides, i.e., gag and gal-pol). In its uninhibited state, HIV aspartic protease cleaves the polypeptides creating functional HIV proteins and enzymes. Antiretroviral PIs effectively interrupt the HIV life cycle as they prevent the formation of HIV virions that would infect further host cells. HCV is an RNA virus but not a retrovirus. PIs active against HCV bind to non-structural protein 3-4A (NS3-4A), which is essential for the HCV life cycle as it cleaves HCV polypeptides into functional viral proteins. Nirmatrelvir targets 3C-like protease, the main protease in coronaviruses. Viral strains resistant to protease inhibitors may emerge rapidly in patients living with HIV and have also been described for HCV. Resistance is mostly mediated by mutations affecting viral proteases which results in reduced binding site affinity of PIs

crop_square Drugs and spectrum of activity

antiretroviral PIs ('-avir')
  • Ataza­navir
  • Daru­navir
  • Fosam­prenavir
  • Indi­navir
  • Lopi­navir
  • Nelfi­navir
  • Rito­navir
  • Saqui­navir
  • Tipra­navir

anti-HCV PIs ('-previr')
  • Asunaprevir
  • Boceprevir
  • Grazoprevir
  • Glecaprevir
  • Paritaprevir
  • Simeprevir
  • Telaprevir

anti-SARS-CoV-2 PIs
  • Nirmatrelvir (Paxlovid)

crop_square Pharmacokinetics

Pharmacokinetics are especially important in protease inhibitors drug therapy. These drugs undergo significant first-past-metabolism through cytochrome P450 enzymes (i.e., CYP3A4, CYP3A5, CYP2C9). This varies considerably between individual patients, and therapeutic drug levels may not always be achieved. Inhibitors of relevant P450 enzymes, such as ritonavir (low dose) and cobicistat are given to increase serum levels of protease inhibitors (‘pharmacokinetics booster’). Elimination half-lives tend to be shorter for antiretroviral PIs. Most PIs are highly protein-bound and are, to the largest part, excreted in the faeces.

crop_square Adverse drug effects

Most PIs may cause gastrointestinal symptoms. Antiretroviral PIs may cause hyperglycaemia and type 2 diabetes mellitus, lipodystrophy, and renal complications among others. Adverse effects of PIs active against HCV include skin rashes, hyperbilirubinaemia and neutropenia.