Modifiers of the post-translational biotransformations

The proteins synthesized by ribosomes become functional only after a certain number of post-translational modifications such as hydrolysis by proteases and transport to their sites of activity. We will study here the post-translational modifications which are currently known to be drug targets.

HIV protease inhibitors, inhibition of viral maturation

The main steps of the replication of the human immunodeficiency virus, HIV: are summarized as follows

  • attachment of the virus to the CD4+T-cell,
  • entry of the virus into the cell,
  • uncoating making viral RNA available,
  • transcription of viral RNA into proviral DNA through reverse transcriptase,
  • integration of the proviral DNA into the genome of the cell-host through integrase,
  • transcription into RNA,
  • translation in nonfunctional polyproteins,
  • post-translational biotransformations leading to mature proteins through the protease
  • formation of a virus by assembly of RNA and proteins. The virus constitutes a bud and is released from the cell-host.

The step which interests us here is inhibition of the HIV protease.

HIV transmits its information by three main genes called gag, pol. and env which codes for proteins necessary to its replication. The genes gag and pol. code for the polyprotein gag and the polyprotein gag-pol. This latter contains a protease which, by autocatalysis is detached from the polyprotein and is dimerized (homodimer), which makes it functional. It then hydrolyzes the polyproteins to release active protein fragments which are in particular: reverse transcriptase (transcription of RNA into DNA), integrase ensuring the insertion of the proviral DNA in the genome of the cell-host, a ribonuclease, other proteins which will constitute the capsid, the nucleocapsid. The gene env codes for proteins of the viral membrane like Gp120 and Gp41.


Inhibition of the viral protease induces the production of immature, non-infectious viral particles, the replication of the virus is inhibited by lack of functional proteins. A systematic research made it possible to select specific inhibitors of viral protease, i.e. practically without effect on human proteases such as renin, cathepsin and elastase.

These viral protease inhibitors appeared effective in the treatment of HIV infections. Their administration induces a decrease of the viral load and an increase in the number of CD4+, lymphocytes, the most affected by the HIV infection. However a resistance to the effect of the protease inhibitors develops quickly when they are given alone. To avoid or delay the advent of this resistance, an inhibitor of the viral protease is never used alone but in combination with one or two other drugs, generally reverse transcriptase inhibitors.

The HIV protease inhibitors are ritonavir (Norvir*), saquinavir (Invirase*, Fortovase*), indinavir (Crixivan*), nelfinavir (Viracept*), amprénavir (Agenerase*), atazanavir (Reyataz*). These inhibitors are pseudopeptides. Among these inhibitors, saquinavir, because its low bioavailability, appears less active but a new presentation, FORTOVASE* has a better bioavailability than the old one, INVIRASE*. Its bioavailability is moreover increased when it is taken during meals. Lopinavir is a protease inhibitor which is marketed combined with ritonavi (Kaletra*). Tipranavir (Aptivus*) is protease inhibitor which is prescribed with low-dose ritonavir. It has many adverse effects, in particular hepatic ones.

Concerning pharmacokinetics, HIV protease inhibitors are administered by oral route and are metabolized by the P450 cytochromes, in particular CYP 3A4. Their bioavailability, according the product, can be or not modified by food intake and their metabolism modified by the intake of other drugs. Because of the diversity of the possible interactions, it is necessary to attentively consult the monograph of each inhibitor before prescribing it. Schematically one can observe:

They are used for the treatment of HIV infections in combination with the other antiviral drugs.

Various adverse effects, digestive, neurosensory, cutaneous sometimes severe, have been indexed. Another undesirable effect is the advent of a cross resistance between protease inhibitors. Moreover, indinavir can give a lithiasis of the biliary tracts by crystallization resulting in lumbar pains, with or without hematuria .

Other viral protease inhibitors are under development such as inhibitors of protease of the hepatitis C virus.

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  Last update : July 2009  
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