HIV protease inhibitor

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HIV protease inhibitors , usually called protease inhibitors or protease inhibitors for short , are drugs that inhibit the enzyme HIV protease of the human immunodeficiency virus (HIV).

chemistry

With the striking exception of tipranavir , all clinically used HIV protease inhibitors are characterized by a peptide- like structure and are therefore also referred to as peptidomimetics . Their structure is based on the structure of the recognition sequence of HIV proteases. HIV protease inhibitors are stable analogs of the transition state of the recognition sequence during the cleavage reaction of the substrate by HIV proteases. Peptidomimetic HIV protease inhibitors show numerous changes compared to their model. The peptide bonds are stabilized or exchanged to protect against cleavage. Lipophilic substituents improve the pharmacokinetic properties and make them more useful as a drug.

How the protease inhibitors work

Protease inhibitors occupy the binding site of the substrate (precursor protein) on the enzyme (protease) and prevent it from developing its effect. The correct virus components can no longer be produced, the virus replication cycle is interrupted.

There are also proteases in the natural metabolism , such as renin , cathepsin D, elastase and factor Xa . However, these are so different from the viral protease that they are not impaired in their effectiveness by HIV protease inhibitors.

HIV protease

It is an enzyme that is encoded in viral RNA . It plays a crucial role in the formation of new viruses, as it catalyzes the cutting up of so-called precursor proteins . The HIV virus requires a number of proteins in order to spread, which are first synthesized in the form of these precursor proteins during reproduction. Only the fragments of this large protein are then used to assemble new virus particles. If the function of the HIV protease is suppressed by inhibitors, the precursor protein cannot be cut or only cut at the wrong places, and the necessary functional building blocks for successful virus reproduction are missing.

The enzyme splits the non- functional polyproteins, especially in the case of hydrophobic and aromatic amino acids and proline , in the P2 region mainly asparagine , in the P1 region tyrosine and phenylalanine and in the P1 'region proline.

indication

Protease inhibitors are approved for the treatment of HIV infections. They are usually used in combination with other antiretroviral drugs ( NRTIs , NNRTIs ). A major disadvantage in practice is the high dosage of these drugs. In order to obtain the effective dose, several tablets must be taken two to three times a day. The trend was therefore to increase the bioavailability of the individual representatives or to develop better dosage forms.

development

The inhibition of the viral protease was achieved by trying to create a high affinity for the catalytic center of the HIV protease by replicating the structure of the peptide , but at the same time by modifying the structure so that it cannot be cleaved in the gastrointestinal tract .

First generation

The first representative on the market was Saquinavir (first registered in 1995). This drug had the disadvantage of a very low bioavailability , which is why very high doses (divided into several tablets) had to be taken at intervals of eight hours, which should be observed as precisely as possible. The second protease inhibitor indinavir (first approval in 1996) did not bring any improvement in this regard.

Second generation

Since the antiretroviral combination therapy is a lifelong treatment, modifications were desired that lead to improved patient compliance , i.e. more comfortable use. The third representative, ritonavir (first approved in 1996), met this requirement for the first time. Ritonavir is a strong inhibitor of the cytochrome P450 system in the liver , which catalyzes the breakdown of lipophilic foreign substances in the organism. This made it possible to keep the plasma level of the active ingredient at a higher level and to reduce the dose. Today it is common practice to combine protease inhibitors with ritonavir in low doses and thus to reduce the total dose of active ingredient.

Third generation

Another problem is the development of resistance of HIV strains to protease inhibitors. Due to the similar structure and the same mechanism of action, cross-resistance usually occurs , that is, if the virus is resistant to a protease inhibitor, the virus is also resistant to the other representatives is no longer inhibited. The fourth representative in this series, nelfinavir (first approved in 1997), presented an alternative for the first time in this case. Also amprenavir (Year 1999) showed a lower tendency to cross-resistance, but this drug by its highly lipophilic character has a distinct weakness with respect to absorption from the gastrointestinal tract. As a result, correspondingly high doses had to be administered. The long half-life of amprenavir, which allowed a twice dose per day, proved to be advantageous. Lopinavir was approved in 2001 . This active ingredient is combined with ritonavir (in the same tablet), which has resulted in a significant dose reduction. With atazanavir , a representative had been available since 2003 that even allowed a single dose per day. The manufacturer of amprenavir developed this drug into a so-called prodrug . The disadvantage of poor absorption was removed by a small modification. Fosamprenavir (first registered in 2004) is, so to speak, a vehicle; esterification with phosphoric acid made amprenavir more soluble in water and is therefore better absorbed into the blood. The result was a significant reduction in the dose.

Fourth generation

Tipranavir heralded the latest generation of protease inhibitors (first approval in 2005). This substance no longer shows the previous peptide structure and thus differs significantly from the older representatives. The advantage is that it works well with HIV strains that have developed resistance to protease inhibitors. However, tipranavir apparently affects the metabolism in the liver to a more complex extent, which manifests itself in various, sometimes life-threatening side effects . As a result, the application is also severely restricted. Another example is darunavir .

General side effects

Symptoms of the gastrointestinal tract, such as nausea, abdominal pain and diarrhea, are relatively common when treated with all representatives of protease inhibitors. Occasionally you can see changes in certain laboratory values, for example of transaminases . Noteworthy, since all protease inhibitors are affected, their influence on the metabolism by the liver.

Effects on cytochrome P450

All protease inhibitors are more or less potent inhibitors of the cytochrome P450 system (mainly CYP3A4). The cytochrome P450 system consists of various enzymes, occurs in high density in the liver and has the task of freeing the organism from foreign substances that are particularly lipophilic (fat-soluble). The excretion of very many drugs takes place with the inclusion of this mechanism. If the system is now inhibited, as happens by protease inhibitors and other substances, unexpectedly high doses of these lipophilic substances remain in the body for longer than usual and can lead to unwanted reactions (overdosing). The use of various drugs such as antiarrhythmics , benzodiazepines and contraceptives together with protease inhibitors is therefore extremely problematic.

literature

Web links

Individual evidence

  1. ↑ G. Abbenante, DP Fairlie: Protease inhibitors in the clinic . In: Med Chem . tape 1 , no. 1 , January 2005, p. 71-104 , PMID 16789888 .