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Many major physiological processes depend on regulation of proteolytic enzyme activity and there can be dramatic consequences when equilibrium between an enzyme and its substrates is disturbed. In this prospective, the discovery of small-molecule ligands, like protease inhibitors, that can modulate catalytic activities has an enormous therapeutic effect.〔Cuccioloni, M. et al. (2009) Natural Occurring Polyphenols as Template for Drug Design. Focus on Serine Proteases. ''Chemical biology and drug design''. 74;1-15.〕 Hence, inhibition of the HIV protease is one of the most important approaches for the therapeutic intervention in HIV infection〔Chen, X. et al. (2003) Synthesis and SAR Studies of Potent HIV Protease Inhibitors Containing Novel Dimethylphenoxyl Acetates as P2 Ligands. Bioorganic & Medicinal Chemistry Letters. 13;3657-3660.〕 and their development is regarded as major success of structure-based drug design.〔Adachi, M. et al. (2009) Structure of HIV-1 protease in complex with potent inhibitor KNI-272 determined by high-resolution X-ray and neutron crystallography. Proceedings of the national academy of sciences of the United States of America. 12; 4641-4646〕 They are highly effective against HIV〔Yanchunas, J. et al. (2005) Molecular Basis for Increased Susceptibility of Isolates with Atazanavir Resistance-Conferring Substitution I50L to Other Protease Inhibitors. ''Antimicrobial Agent and Chemotherapy''. 40;3825-3832.〕 and have, since the 1990s, been a key component of anti-retroviral therapies for HIV/AIDS.〔Brower, E.T., et al. Inhibition of HIV-2 protease by HIV-1 protease inhibitors in clinical use. ''Chemical Biology & Drug Design''. 71;298-305.〕 == History == Human immunodeficiency virus (HIV) is a lentivirus that has two major species, HIV-1 which causes the majority of the epidemic, and HIV-2, a close relative whose distribution is concentrated in western Africa. HIV infection was first described in 1981 in San Francisco and New York City. In 1985, HIV was identified as the causative agent of acquired immune deficiency syndrome (AIDS) and its complete genome was immediately available. This knowledge paved the way for the development of selective inhibitors.〔 HIV-2 carries a slightly lower risk of transmission than HIV-1 and infection tends to progress more slowly to AIDS.〔 In common usage HIV usually implies HIV-1. HIV-1 protease is one of the best known aspartic proteases, and an attractive target for the treatment of AIDS. After the discovery of HIV protease it only took 10 years for its first inhibitor to reach the market. The first reports of highly selective antagonists against the HIV protease were revealed in 1987. Phase I trials of saquinavir began in 1989 and it was the first HIV protease inhibitor to be approved for prescription use in 1995. Four months later, two other protease inhibitors, ritonavir and indinavir, were approved.〔 In 2009, ten protease inhibitors have reached the market for treatment against HIV but one protease inhibitor, amprenavir, was withdrawn from the market in 2004.〔 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「Discovery and development of HIV-protease inhibitors」の詳細全文を読む スポンサード リンク
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