Protease Inhibitors

The discovery of HIV protease inhibitors (PIs) were the most important for controlling HIV infection. Highly Active Antiretroviral Therapy (HAART) with the presence of HIV PIs in patient management has had an intense impact on the clinical history of HIV. But, HAART has been linked to many complications such as cardiovascular and metabolic syndrome in patients.

Protease inhibitors are a classified as a class of antiretroviral drugs used in the treatment of HIV. it is also known to prevent activation of an HIV enzyme called this protease is synthesized to form new viral particles and that is how HIV spreads to uninfected cells of the body. However, protease inhibitors only produce noninfectious viral particles and examples of these are, saquinavir, ritonavir and indinavir.

In 1995 the first protease inhibitor was produced, saquinavir, is a peptidomimetic hydroxyethylamine. It is a transition state analogue of a native substrate of the protease. The study is that HIV-1 protease cleaves the sequences that have dipeptides Tyr-Pro or Phe-Pro was the critical design criterion. Then the accumulation of the decahydroisoquinoline (DIQ) group and this was best modification that led to the discovery of saquinavir because the substituent improves aqueous solubility and potency by minimizing the conformational freedom of the inhibitor. Saquinavir is successful against both HIV-1 and HIV-2 and is frequently tolerated but elevated serum concentration levels are not seen.

In 1996, Ratanovir was marketed. Ratanovir was created by Abott Laboratories to fit the C2-symmetry in the necessary site of the protease. They began with compounds that was active against the virus but has poor bioavailability, so the drug was altered, for example the terminal phenyl residues were taken out and pyridyl groups put in place to add water solubility. Thus Ratanovir was formed. It is not used as a single drug dose therapy due to gastrointestinal side effects but because of its strong inhibition on cytochrome P450 it is used in combination therapy that is pharmacokinetic boosting.

In 1996 a new drug hit the market and was based on the molecular modelling and the X-ray crystal structure of the inhibited enzyme complex. This drug is Indinavir and is a peptidomimetic hydroxyethylene HIV protease inhibitor. The last phenyl group of the structure contributes to icrease potency by hydrophic binding. It is an analogue of the phenylalanine-proline cleavage site of the HIV Gag-polyprotein.

In 1997, a drug, Nelfinavir, was formed and this was the first nonpeptidomimetic drug on the market. It is an iterative protein cocrystal structure analysis of peptidic inhibitors, and parts of the inhibitors were substituted by nonpeptidic substituents. Nelfinavir has a novel 2-methyl-3-hydroxybenzamide group, compared to saquinavir which has a carboxyl terminal with the same DIQ group. This drug was the first to be used for peditric AIDS.

Two years later in 1999, a new drug was formed, Amprenavir. It shares similar features with the other protease inhibitrs but it is a N,N-disubstituded amino-sulfonamide nonpeptide HIV protease has different functional groups on its terminals but same structure as saquinavir. Amprenavir has less chirla structures therefore it is easier to synthesize and produce better aqueous solubility, which thus produces effective oral bioavailability. However, amprenavir was discontinued from the market in 2004 because a prodrug, fosamprenavir was superior in many aspects. Fosamprenavir was made in 2003, the solubility and bioavailability is better than Amprenavir and there are fewer pills to induce.

Lopinovir was designed in the year 2000 and was made to diminish the interactions of the inhibitor with Val82 of the HIV-1 protease, a residue that is often mutated in the drug resistant strains of the virus. It is the same as Ritanovir except ratanovir has a 5-thiazolyl terminal group in while lopinavir has a phenoxyacetyl group and the 2-isopropylthiazolyl group.

In 2005, Tipranovir was introduced. It is a nonpeptidic HIV-1 protease inhibitor, and was created from nonpeptidic courmaarin template. Through screening at high levels its antiprotease activity was discovered. This sulfonamide containing 5, 6-dihydro-4-hydroxy-2-pyrone has been found from screenings of 3-substituted coumarins and dihydropyrones. It contains broad antiviral activity against multiple protease inhibitor resistant HIV-1.

In 2006, an analogue of Amprenavir was formed. It had a critical change at the terminal tetrahydrofuran (THF) group. The drug, Darunavir, consisted of two THF groups fused in the compound instead of the one THF group. Because of the two THF groups it is more effective than Amprenavir.With this structural modification, the stereochemistry surrounding the bis-THF moiety confers orientational alterations, which allows for continuous binding with the protease which has already developed a resistance for amprenavir.

Analysis of drugs

Single-agent treatment with a protease inhibitor can form the selection of drug-resistant HIV. Thus, protease inhibitors are usually used in combination with other antiretroviral agents, particularly agents that perform at different points in the life cycle of HIV. For example, the use of a protease inhibitor in combination with a reverse transcriptase inhibitor, which prevents the conversion of retroviral RNA into DNA, suppresses HIV replication more effective than the drug by itself. The most efficient combination therapy that is used to suppress the surfacing of resistant virus is highly active antiretroviral therapy (HAART), which is a combination of three or more reverse transcriptase and protease inhibitors. Missing doses also affects absorptions because studies have proved that the virus changes so the medication may not be as effective as before.

Drugs are used in combination therapy and the most favourable of the protease inhibitors are interactions of cytochrome P450 isoenzymes and also multi-drugs that transport P-glycoprotein. Most of the combinations contain Ritonavir because of the drugs properties to inhibit cytochrome 3A4 enzyme. Combination of ritonavir, low dose, with a protease inhibitor results in pharmacokinetic properties being increased immensely. A few comibinations of drug therapy is listed below:

Tipranavir + ritonavir

Lopinavir + ritonavir

Darunavir + ritonavir

Fosamprenavir + ritonavir

Saquinavir + ritonavir

Most of these drugs combinations listed have no dose limitations but must be used cautiously. Patients should be aware of side effects and the most common is diarrhea and nausea. Missed doses causes a problem for protease inhibitors as a missed dose can cause alterations and changes in the HIV disease and therefore the drugs will be inadequate for treatment or less effective.

In early stages single does is given but for most chronic stages of HIV combinations are used especially ritonavir with saquinavir and this is the best possible combination used because of the metabolosing on the P-glycoprotein.


HIV-1 protease inhibitors are potent agents in the therapy of HIV-1 infection. They have inadequate oral absorption and variable tissue distribution, and this complicates the usage of these drugs. Saquinavir has poor bioavailability but the other drugs have good bioavailability. Poor bioavailability leads to poor absorption. The absorption is also based of the physiochemical properties such as solubility and lipophilicity. Some drugs like, saquinavir, ritonavir, indinavir, nelfinavir and amprenavir all undergo first past metabolism. Multiple dosing proved to give a better absorption than single dose therapy because the bioavailability of drugs is improved. Ritonavir absorption increased with an intake of food while indinavir decreased its absorption when administered with a meal high in fat content. Other drugs, food does not really impact absorption the altering of dosage regimens also proves to give better bioavailability which therefore means better absorption. A lot of factors can influence absorptions such as food, other diseases present, if medication is taken on time and at what stage of the disease the person is at, that is chronic or acute, the dose and the dose regimen.


HIV protease inhibitor management can affect the standard stimulatory effect of insulin on glucose and fat storage. Additional, chronic inflammation because of the HIV infection and protease inhibitor management trigger cellular homeostatic stress responses that lead to adverse effects on intermediary metabolism. The physiologic conclusion is that the total adipocyte storage capacity is decreased, and thus remaining adipocytes resist more fat storage. This cause a pathologic cycle of lipodystrophy and lipotoxicity, a proatherogenic lipid profile, and a clinical phenotype of increased central body fat distribution similar to the metabolic syndrome. the use of protease inhibitors for long term can results in abnormal fat distribution in the body which can later lead to further sickness, that is why a healthy diet is recommended. This abnormal fat distribution is usually caused with the drug indinavir.


A relationship was found between cytochrome 3A4 inhibitory potency and metabolic stability, that is compounds were more potent for the cytochrome 3A4 enzyme inhibition and were usually more metabolically stable. Furthermore the compounds presented two clusters which are defined as the distinct type of substrate induced P450 binding spectra. The compounds with binding spectra type two were more metoblic stable and stable for the enzyme cytochrome 3A4 inhibition compared to that of the type one.Protease inhibitors induce effects of insulin resistance, dysregulation of lipid metabolism as well as inflammation. These are all part of cardiovascular and metabolic diseases. The metabolism of protease inhibitors is mostly perfomed in the liver as well as the intestines by the enzyme cytochrome 3A4. Occasionally the same protease inhibitor is affected by multiple enzymes. Due to this the metabolism of other drugs for other diseases and protease inhibitors are also affected. Protease inhibitors boosters like Norvir, the strongest effect on enzymes, determine how fast the other protease inhibitors get eliminated. Because of the metabolism of the liver combination therapy is used to lower the amount of pill intake but still have good bioavailability to cause an effect on its receptors and cells.

Source: Essay UK -

About this resource

This Science essay was submitted to us by a student in order to help you with your studies.

Search our content:

  • Download this page
  • Print this page
  • Search again

  • Word count:

    This page has approximately words.



    If you use part of this page in your own work, you need to provide a citation, as follows:

    Essay UK, Protease Inhibitors. Available from: <> [01-06-20].

    More information:

    If you are the original author of this content and no longer wish to have it published on our website then please click on the link below to request removal: