HIV protease inhibitors: antiretroviral agents with anti-inflammatory, anti-angiogenic and anti-tumour activity

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Abstract
Despite mild toxicity and adverse effects, human immunodeficiency virus (HIV) protease inhibitors (PIs), used in combination with reverse transcriptase nucleoside inhibitors (NRTIs), have turned AIDS into a chronic, manageable disease. Such combination therapy, known as highly active antiretroviral therapy (HAART), efficiently suppresses HIV replication leading to immune restoration in HIV-infected patients. HIV PIs act by blocking the HIV aspartyl protease, a viral enzyme that cleaves the HIV gag and gag-pol polyprotein backbone at nine specific cleavage sites to produce shorter, functional proteins. Three of the nine cleavage reactions occur between a phenylalanine or a tyrosine and a proline. Strikingly, none of the known mammalian endopeptidases cleaves before a proline; for this reason, most HIV PIs have been designed to mimic the phenylalanine–proline peptide bond. This confers a remarkable specificity of action to HIV PIs and, with short-term treatment, they show only mild side-effects and a tolerable toxicity. 1

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