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- W91478412 abstract "Abstract The protease encoded within the pol gene of human immunodeficiency virus (HIV) is essential for maturation of the newly budded virion to an infectious viral particle. For this reason, inhibitors of the HIV protease have been developed as possible drugs for treatment of acquired immunodeficiency syndrome (AIDS), a condition associated with HIV infection. The viral protease is a paradigm for rational drug design. It is a member of a well-characterized mechanistic set of proteases, the aspartyl enzymes, and therefore much is known by inference regarding its structure and mechanism. Yet, it is also unique among all known proteases in having a dimeric structure, and accordingly, it offers a selective target for drugs in humans. The monomeric units, identical, 99-residue polypeptides, each contribute symmetrically to the catalytic site, and the enzyme is a C2-symmetric dimer. At the time of this writing, hundreds of structures have been solved crystallographically for the HIV-1 protease, both alone and in complexes with a wide spectrum of inhibitors, so the enzyme ranks among the best understood in terms of both structure and mechanism. The protease is also unique in its specificity, being able to hydrolyze almost any peptide bond, given an optimal distribution of amino acids in P4 through P4′, and accessibility to the bond in question. This specificity has been the basis for early development of protease inhibitors with noncleavable transition state inserts replacing the scissile bond pair. However, if an HIV protease inhibitor is to be successful as a drug for treatment of AIDS, it must not only be potent in blocking enzyme activity, but it must satisfy the usual criteria that define a useful therapeutic agent. The last 5 years have witnessed a transition from peptide-like inhibitors that are generally marginal as drugs because of poor solubility and/or bioavailability, to smaller, nonpeptide, organic molecules with enhanced pharmacokinetic properties. The process of protease inhibitor development has encompassed everything from serendipitous, classical screening approaches to de novo design. The latter achievement has been possible through an iterative cycle of crystallographic analysis, computer-assisted refinement and prediction, organic synthesis, and biological assays. In fact, this whole process of discovery of drugs designed to target the HIV protease represents a powerful alliance among numerous disciplines, including virology, biochemistry, molecular biology, X-ray crystallography, computer modeling, medicinal chemistry, pharmacology, and applied medicine. This chapter focuses on this process, highlighting those protease inhibitors that have been brought forward for clinical trials, and providing some early results in the clinics. Some discussion is also included of mutations in the protease, which have been documented in viral strains that show resistance to protease inhibitor drugs." @default.
- W91478412 created "2016-06-24" @default.
- W91478412 creator A5000309168 @default.
- W91478412 creator A5016822525 @default.
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- W91478412 date "1996-01-01" @default.
- W91478412 modified "2023-10-12" @default.
- W91478412 title "Discovery and design of HIV protease inhibitors as drugs for treatment of aids" @default.
- W91478412 cites W1484847336 @default.
- W91478412 cites W1492569591 @default.
- W91478412 cites W1499808375 @default.
- W91478412 cites W1512060784 @default.
- W91478412 cites W1514209943 @default.
- W91478412 cites W1534977381 @default.
- W91478412 cites W1537553846 @default.
- W91478412 cites W1561712938 @default.
- W91478412 cites W1577225039 @default.
- W91478412 cites W1593098626 @default.
- W91478412 cites W1602496180 @default.
- W91478412 cites W1767745975 @default.
- W91478412 cites W1878111742 @default.
- W91478412 cites W1965349185 @default.
- W91478412 cites W1966952510 @default.
- W91478412 cites W1969899610 @default.
- W91478412 cites W1970106134 @default.
- W91478412 cites W1973696741 @default.
- W91478412 cites W1974224443 @default.
- W91478412 cites W1976482662 @default.
- W91478412 cites W1977249582 @default.
- W91478412 cites W1977790220 @default.
- W91478412 cites W1979100242 @default.
- W91478412 cites W1981491253 @default.
- W91478412 cites W1981555301 @default.
- W91478412 cites W1982071925 @default.
- W91478412 cites W1983066351 @default.
- W91478412 cites W1985469117 @default.
- W91478412 cites W1986348937 @default.
- W91478412 cites W1986671430 @default.
- W91478412 cites W1989463313 @default.
- W91478412 cites W1989475707 @default.
- W91478412 cites W1991448988 @default.
- W91478412 cites W1991781846 @default.
- W91478412 cites W1991923613 @default.
- W91478412 cites W1995246525 @default.
- W91478412 cites W1995396220 @default.
- W91478412 cites W2002400107 @default.
- W91478412 cites W2003467761 @default.
- W91478412 cites W2010087817 @default.
- W91478412 cites W2012108232 @default.
- W91478412 cites W2014303214 @default.
- W91478412 cites W2023133891 @default.
- W91478412 cites W2024568805 @default.
- W91478412 cites W2026802618 @default.
- W91478412 cites W2027168767 @default.
- W91478412 cites W2027877318 @default.
- W91478412 cites W2028124297 @default.
- W91478412 cites W2030402747 @default.
- W91478412 cites W2035241906 @default.
- W91478412 cites W2035286938 @default.
- W91478412 cites W2037695285 @default.
- W91478412 cites W2038350697 @default.
- W91478412 cites W2039695661 @default.
- W91478412 cites W2040938282 @default.
- W91478412 cites W2044028507 @default.
- W91478412 cites W2045408268 @default.
- W91478412 cites W2048448899 @default.
- W91478412 cites W2050498291 @default.
- W91478412 cites W2054728806 @default.
- W91478412 cites W2056704605 @default.
- W91478412 cites W2060740730 @default.
- W91478412 cites W2063061020 @default.
- W91478412 cites W2063950143 @default.
- W91478412 cites W2065693353 @default.
- W91478412 cites W2069146496 @default.
- W91478412 cites W2069366448 @default.
- W91478412 cites W2069764755 @default.
- W91478412 cites W2071265228 @default.
- W91478412 cites W2075135942 @default.
- W91478412 cites W2076503226 @default.
- W91478412 cites W2080786231 @default.
- W91478412 cites W2085318243 @default.
- W91478412 cites W2086003834 @default.
- W91478412 cites W2086462809 @default.
- W91478412 cites W2089019538 @default.
- W91478412 cites W2092790774 @default.
- W91478412 cites W2093217552 @default.
- W91478412 cites W2096612110 @default.
- W91478412 cites W2104639107 @default.
- W91478412 cites W2115853658 @default.
- W91478412 cites W2115869555 @default.
- W91478412 cites W2123166384 @default.
- W91478412 cites W2128827201 @default.
- W91478412 cites W2132185205 @default.
- W91478412 cites W2133135980 @default.
- W91478412 cites W2141112299 @default.
- W91478412 cites W2141385111 @default.
- W91478412 cites W2146946460 @default.
- W91478412 cites W2153150300 @default.