Protease inhibitor (pharmacology)
HIV protease inhibitors, often abbreviated to protease inhibitors or protease inhibitors are drugs which inhibit the HIV protease enzyme of human immunodeficiency virus ( HIV).
- 6.1 influence of cytochrome P450
Chemistry
With the striking exception of tipranavir, all clinically used HIV protease inhibitors characterized by a peptide-like structure and are therefore also referred to as peptidomimetics. Its structure is based on the structure of the recognition sequence of HIV proteases. HIV protease inhibitors provide this stable analogues of the transition state of the recognition sequence during the cleavage reaction of the substrate by HIV proteases dar. Peptidomimetic HIV protease inhibitors have, in comparison to its archetype, numerous changes. The peptide bonds are stabilized or replaced for protection against cleavage. Lipophilic substituents improve the pharmacokinetic properties and make them usable as a drug.
Operation of the protease inhibitors
Protease inhibitors occupy the binding site for the protease to the substrate ( precursor protein) and prevent it can take effect. It can be produced not the correct virus components, the viral replication cycle is interrupted.
There are also natural metabolism proteases such as renin, cathepsin D, elastase, factor Xa. However, these differ so much that they are affected by HIV protease inhibitors are not in their action of the viral protease.
HIV protease
Is an enzyme which is encoded in the viral RNA. In the formation of new viruses, it plays a crucial role, since it catalyzes the cutting of so-called precursor proteins. HIV needs a number of proteins which are initially synthesized in the form of multiplication in these precursor proteins for its propagation. It was only from the fragments of this large protein new virus particles are then assembled. If the function of the HIV protease inhibitors suppressed, so the precursor protein can not be severed or just in the wrong places and for successful viral replication, lack the necessary functional components.
The enzyme cleaves the polyproteins nonfunctional especially with hydrophobic and aromatic amino acids, and proline in the P2 region, especially asparagine, in the P1 region tyrosine and phenylalanine in the P1 ' proline region.
Indication
Protease inhibitors have been approved for the treatment of HIV infections. They usually come in combination with other antiretroviral drugs ( NRTIs, NNRTIs ) are used. A major drawback in practice, the high dosage of these drugs dar. to ensuring the effective dose must be taken to get two to three times a day several tablets. The development, therefore, has been to increase the bioavailability of the individual representatives or to develop better forms.
Development
The inhibition of the viral protease was achieved by trying to make them by planting the structure of the peptide has a high affinity to the catalytic site of HIV protease, but at the same time to modify the structure so that it can not be digested in the gastrointestinal tract.
First generation
The first representative on the market was saquinavir ( Registered 1995). This drug had the disadvantage of a very low bioavailability, which is why very high doses were (spread over several Tablets) in as exact stipulated intervals of eight hours to take. The second protease inhibitor indinavir ( Registration date 1996 ) did not yield any improvement in this respect.
Second generation
Since it is in the combination antiretroviral therapy for life-long treatment, modifications were desirable that lead to improved patient compliance, thus more comfortable application. The third representative, ritonavir ( Registration date 1996 ), this requirement met for the first time. Ritonavir is a potent inhibitor of the cytochrome P450 system in the liver, which catalyzes the degradation of lipophilic impurities in the organism. This has made it possible to keep the plasma level of the drug at a higher level and to reduce the dose. Today it is customary to combine with ritonavir protease inhibitors in low doses, thereby reducing the total drug dose.
Third generation
Another problem is the development of resistance of HIV strains to protease inhibitors dar. Due to the similar structure and the same mechanism occurs mostly cross-resistance, that is, when resistance to a protease inhibitor, the virus is also resistant to the other representatives and is no longer inhibited. The fourth member of this series, nelfinavir ( Registered 1997), presented for this case for the first time an alternative. Also amprenavir ( Registered 1999) showed a lower tendency to cross-resistance, but this drug has its strong lipophilic character of a significant weakness with respect to absorption from the gastrointestinal tract. Consequently, we had to administer high doses accordingly. Advantageously, proved to be the long half-life of amprenavir, which allowed a two-time dose per day. 2001 lopinavir was approved. This ingredient is fixed ( in the same tablet) combined with ritonavir, resulting in a significant dose reduction result. With atazanavir in 2003 was a representative available that allowed even a single dose per day. The manufacturer of amprenavir developed this drug to a so-called prodrug on. It acknowledged the disadvantage of poor absorption by a small modification to the side. Fosamprenavir ( Registered 2004) is as it were a vehicle through esterification with phosphoric amprenavir was more soluble in water and is more effectively absorbed into the blood. A significant reduction of the dose was the result.
Fourth generation
The latest generation of the protease inhibitors tipranavir rang a ( Registered 2005). This substance does not show the previous peptide structure and thus is significantly different from the older representatives. The advantage is the good effect of HIV strains that have developed resistance to protease inhibitors. However, tipranavir influenced apparently more complicated dimensions metabolism in the liver, which manifests itself in various, sometimes life- threatening side effects. Accordingly, the application is greatly limited.
General side effects
Complaints of the gastrointestinal tract, such as nausea, abdominal pain and diarrhea are relatively common in treatment with all representatives of the protease inhibitors. Occasionally, changes in certain laboratory tests to determine, for example, of transaminases. Noteworthy, as all protease inhibitors are concerned, is their influence on the metabolism by the liver.
Influence of cytochrome P450
All protease inhibitors are more or less potent inhibitors of the cytochrome P450 system ( primarily CYP3A4 ). The cytochrome P450 system consists of various enzymes, comes in great density in the liver before and has the mission to rid the body of foreign substances, which have particularly lipophilic (fat soluble) character. The excretion of many drugs is carried out with the involvement of this mechanism. If the system is now inhibited, as is done by protease inhibitors and other substances so unexpectedly high doses of these lipophilic substances remain for a longer time than usual in the body and can lead to unwanted reactions ( overdose). The use of various drugs such as antiarrhythmics, benzodiazepines, and contraceptives together with protease inhibitors is therefore extremely problematic.