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Document 1 Inhibitors of HIV-1 Protease Krzysztof Appelt Agouron Pharmaceuticals, Inc., San Diego, California I. Introduction Page 1 Since the discovery of human immunodeficiency virus (HIV) as the causative agent of acquired immunodeficiency syndrome (AIDS), perhaps the largest and most powerful consortium of scientists ever assembled to tackle a single disease has been brought to bear on the problem of AIDS and its treatment. From an unprecedented wealth of information regarding the molecular biology and virology of HIV collected in recent years, it became possible to identify numerous intervention points in the viral life cycle that could be exploited in the development of drugs for AIDS therapy (for reviews see Reference 1, 2, and 3). Among these, the virally-encoded enzymes, in particular reverse transcriptase and protease, have emerged as the most popular targets. A separate chapter of this book is dedicated to the description of reverse transcriptase and its inhibitors [4]. For the purpose of introduction only, it should be noted that nucleoside inhibitors of reverse transcriptase (AZT, ddI, ddC, d4T, and 3TC) have been widely used in clinical practice since 1987. Since then it has become apparent that this class of agents, while slowing progression of disease in HIV-infected patients, is limited in both activity and the duration of the clinical responses produced. Therefore in the search for better anti-HIV agents, the focus of effort was expanded to include the search for clinically useful inhibitors of a second viral enzyme, namely the protease. In contrast to reverse transcriptase, for which activity is required prior to the integration of viral genetic information into the host cell chromosomes, the viral protease plays a key role late in the virus life cycle and inhibitors of this enzyme display equal anti-viral activity in chronic and acute infection models in vitro [5]. The HIV protease (HIV PR) is encoded by the 5' portion of the retroviral pol gene, which encodes all replicative enzymes. Viral structural proteins (p24, http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_1.html [2/29/2004 2:14:53 AM]
Document p17, p9, and p7) and replicative enzymes (protease, reverse transcriptase/ RnaseH, and integrase) are translated as either polyprotein P55-GAG, or a larger frameshift product P160-GAG-POL. In the process of virus assembly these polyproteins are proteolytically cleaved by the protease and this processing step, both in its timing and accuracy, is essential for the formation of infectious particles of HIV [6]. It was also shown early on that the inactivation of HIV PR, either by chemical inhibition or certain mutations, leads to the production of immature, noninfectious viral particles [7,8]. Page 2 Structurally HIV PR is a 99-amino-acid protein translated initially as a central part of the P160-GAG- POL polyprotein precursor. The autocatalytic processing from the 160 kDa precursor is poorly understood, but most likely occurs during the process of budding of pre-formed viral particles from the host cell [9]. After release from the precursor polyprotein, HIV PR forms a homodimer and acts in trans to correctly process GAG and GAG-POL polyproteins—a process required for formation of the viral capsid and nucleoprotein core. Retroviral proteases such as HIV PR are the latest additions to the wellstudied family of aspartic proteases. This family of enzymes, which includes, among others, proteases such as pepsin, renin, and cathepsins D and E, has been intensely studied in the past, and the knowledge gained from studies of these enzymes allowed early inferences as to the structure and function of the dimeric HIV PR. Moreover, the intensive effort over the past two decades to make inhibitors of human renin provided impetus for the early design of inhibitors of HIV PR. In fact, some of the renin inhibitors have turned out to be effective inhibitors of retroviral aspartic proteases as well and have served as the starting point for drug design. As a result of this many early inhibitors of HIV PR were peptidyl in nature and the best known example of such compounds is Ro31-8959, better known as saquinavir, a hydroxyethylaminecontaining mimetic of a hexapeptide substrate [10]. This potent inhibitor of HIV PR was discovered using a substrate-based rational approach to drug design and displays extremely high in vitro activity against clinical isolates and laboratory strains of HIV. Saquinavir has been recently approved by the FDA for the treatment of AIDS in combination with nucleoside inhibitors of reverse transcriptase, and the discovery of this compound was the first breakthrough and the starting point for many other innovative designs. Determination of the crystal structures of HIV PR gave new impetus to the design of novel inhibitors. One measure of the intensity with which new inhibitors were designed or discovered is the total number of crystal structures of inhibitory complexes, currently exceeding 250, that have been determined over the past 5 years. Very detailed crystallographic analysis combined with extensive biochemical characterization and site-specific mutagenesis studies made HIV PR perhaps the best characterized enzyme to date. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_2.html [2/29/2004 2:14:57 AM]
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