Protease inhibitors

Protease inhibitors block the activity of the protease enzyme, which HIV uses to break up large polyproteins into the smaller pieces required for assembly of new viral particles. While HIV can still replicate in the presence of protease inhibitors, the resulting virions are immature and unable to infect new cells.

The licensed protease inhibitors are:

  • amprenavir (Agenerase)
  • atazanavir (Reyataz)
  • darunavir (Prezista)
  • fosamprenavir (Telzir, Lexiva)
  • indinavir (Crixivan)
  • lopinavir/ritonavir (Kaletra, Aluvia)
  • nelfinavir (Viracept)
  • ritonavir (Norvir)
  • saquinavir (Invirase)*
  • tipranavir (Aptivus).

Protease inhibitors are metabolised by enzymes in the liver and can interact with other medications by speeding up or slowing down their processing in the body. Ritonavir, in particular, is a strong inhibitor of these liver enzymes and slows the processing of many other drugs.

While this normally would be considered a drawback, researchers discovered that a small dose of ritonavir could be used to ‘boost’ blood levels of other protease inhibitors and extend dosing intervals. Kaletra combines in one pill both lopinavir and a boosting dose of ritonavir.

The HIV protease contains a binding pocket into which drugs must fit in order to block the activity of the enzyme. As HIV replicates, constant mutations change the shape of this structure. Some such changes make it impossible for one or more protease inhibitors to bind to the enzyme, resulting in drug resistance.

Second-generation protease inhibitors (atazanavir, darunavir, fosamprenavir, lopinavir, and tipranavir) work against HIV variants that have developed resistance to older drugs in this class. Darunavir and tipranavir differ from the others in that they are synthetic nonpeptidic drugs.

In 2009, Kaletra was given European marketing authorisation for once-daily dosing with an 800mg/200mg co-formulation. Boosted darunavir, dosed once daily at 800mg/100mg, was also given European marketing approval for use in antiretroviral-naive individuals.

Concert Pharmaceuticals has developed a deuterium chemistry platform in which key hydrogen atoms are replaced by deuterium, a heavier relative of hydrogen. They will be developing CTP-518, an analogue of atazanavir, with GlaxoSmithKline, and a phase one trial is due to commence in early 2010. The presence of deuterium slows hepatic elimination, resulting in a longer drug half-life and higher trough levels without the use of a boosting agent, such as ritonavir. The same company also has a patent on a darunavir analogue drug.

GS-8374 (formerly TMC-126), from Gilead Sciences, adds a phosphonate group onto a protease inhibitor. The corresponding prodrug, taken orally, enters the cell and is able to entrap the protease enzyme. In vitro studies indicate a low potential for adverse metabolic effects.1

MK-8122 (formerly PPL-100), developed by Ambrilia and sold to Merck & Co. in 2006, completed a phase I repeat dosing study. Merck put development of this drug on hold in 2008.2

Far more exciting are emerging data concerning three pharmacokinetic (PK)-enhancing agents that, while having no anti-HIV effect on their own, are intended to give protease inhibitors a boost without the metabolic side-effects that often result with ritonavir. These agents are intended for use in fixed-dose combinations for first-line antiretroviral therapy.

Cobicistat (GS-9350) from Gilead Sciences is stable at room temperature, can be dosed once daily, and is in solid form – all qualities that enable its co-formulation with the Gilead investigational integrase inhibitor elvitegravir and Truvada (emtricitabine and tenofovir). There are ongoing phase II clinical trials with GS-9350 for treatment-naive individuals. One is a comparator study of the 'quad' pill versus Atripla (efavirenz/tenofovir/emtricitabine) and the other is a dose-ranging study looking at the efficacy of atazanavir boosted by GS-9350 versus ritonavir.3 4

SPI-452 from Sequoia Pharmaceuticals is another PK enhancer that, in animal studies, was able to boost levels of saquinavir, lopinavir, and atazanavir. In a phase I trial, SPI-452 significantly increased plasma concentrations of the PIs atazanavir and darunavir. Sequoia has filed investigational new drug applications with the US FDA for SPI-425 and the experimental HIV protease inhibitor SPI-256, suggesting it may have plans for a co-formulation that would be an alternative to Kaletra.5 Data on SPI-256 were first introduced in 2006.6

Lastly, the specialist HIV company formed by GlaxoSmithKline and Pfizer, ViiV Healthcare, is continuing development of the PK-enhancer PF-3716539.

* A soft-gel formulation of saquinavir called Fortovase was discontinued.

For further information on specific protease inhibitors, see A to Z of antiretroviral drugs


  1. Callebaut C et al. Profile of GS-8374, a novel phosphonate-containing HIV PI: in vitro antiretroviral activity, toxicity, and resistance. 14th Conference on Retroviruses and Opportunistic Infections; Los Angeles, abstract 491 (poster), 2007
  2. Dandache S et al. In vitro antiviral activity and cross-resistance profile of PL-100, a novel protease inhibitor of human immunodeficiency virus type 1. Antimicrob Agents Chemother 51(11):4036-4043, 2007
  3. Mathias A et al. GS-9350: A pharmaco-enhancer without anti-HIV activity. Sixteenth Conference on Retroviruses and Opportunistic Infections, Montreal, abstract 40, 2009
  4. Ramanathan S et al. Pharmacokinetic boosting of atazanavir with the pharmacoenhancer GS-9350 versus ritonavir. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, abstract A1-1301, 2009
  5. Gulnik S et al. Preclinical and early clinical evaluation of SPI-452, a new pharmacokinetic enhancer. Sixteenth Conference on Retroviruses and Opportunistic Infections, Montreal, abstract 41, 2009
  6. Gulnik S et al. Antiviral activity of SPI-256 against WT and MDR strains. Antivir Ther 11:S31, abstract 26, 2006
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