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Inhibitors of HIV-1 Protease: Current State of the Art 10 Years After their Introduction. From Antiretroviral Drugs to Antifungal, Antibacterial and Antitumor Agents Based on Aspartic Protease Inhibitors

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The introduction of highly active antiretroviral therapy (HAART) in 1996 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 ones, saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir, and the second generation ones, fosamprenavir (the amprenavir prodrug), lopinavir, atazanavir, and tipranavir. Many other compounds are in advanced clinical evaluation, such as among others TMC-114, whereas a lot of different other effective HIV protease inhibitors 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 on 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 (such as for example 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 antitumor agents, as antibacterials (for example against Mycobacterium tuberculosis infection), antifungals (against Candida albicans), antimalarials, antiSARS and anti-influenza agents.

Keywords: HAART; HIV-1; amprenavir; atazanavir; fosamprenavir; indinavir; lopinavir; nelfinavir; ritonavir; saquinavir

Document Type: Research Article


Affiliations: Universita degli Studi di Firenze, Dipartimento di Chimica, Laboratorio di Chimica Bioinorganica, Via della Lastruccia, 3,Rm. 188, I-50019 Sesto Fiorentino (Florence), Italy.

Publication date: November 1, 2007

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.

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