Abstract
Highly active antiretroviral therapy (HAART) has dramatically changed the course of HIV infection. This therapy involves the use of at least three agents from two distinct classes of antivirals: a protease inhibitor (PI) in combination with two nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs); or a non-nucleoside reverse transcriptase inhibitor (NNRTI) in combination with NRTIs. Nine drugs containing PIs are clinically available: the first-generation saquinavir, ritonavir, indinavir, nelfinavir and amprenavir; and the second-generation fosamprenavir (the amprenavir prodrug), lopinavir, atazanavir and tipranavir. Many other compounds are in advanced clinical evaluation, such as darunavir (TMC-114) and brecanavir, among others. Many other effective HIV PIs were reported, mainly by using amprenavir and TMC-114 as lead molecules. The main goals of research in this field are: i) the design of better pharmacological agents, devoid of severe side effects, resistance problems and with simple administration schedules (preferably once-daily); and ii) achieving eradication of the virus and, possibly, a definitive cure of the disease. A review of the pharmacology and interactions of these agents with other drugs is presented here, with emphasis on how these pharmacological interferences may improve the clinical use of antivirals, or how side effects due to PI drugs may be managed better by taking them into account (e.g., ritonavir boosting of other PIs, which reduces dosages and administration schedules of these drugs). Except for being highly effective in the treatment of HIV infection, recent reports showed this class of drugs to be effective as antitumour agents, apoptosis enhancers, antibacterials (e.g., against Mycobacterium tuberculosis infection), antifungals (e.g., against Candida albicans), antimalarials, anti-SARS and anti-influenza agents.
Acknowledgements
Research from author’s laboratories (A Scozzafava and CT Supuran) was financed in part by a grant of the 6th Framework Programme of the European Union (EUROXY project); S Rusconi was supported by grants from the Istituto Superiore di Sanità (ISS), Rome, Italy – III, IV e V Programma Nazionale di Ricerca sull’AIDS (projects n. 40C.80, 40D.74 and 30F.46). Special thanks are addressed to J-Y Winum (Montpellier University, France) for help with drawing some of the structures present in the paper.