Human immunodeficiency virus proteases

Human immunodeficiency virus (HIV) protease is responsible for processing the gag and gagipol gene product that allow for the organization of 

The search for HIV protease inhibitors is unique in the sense that it is one of the first examples of detailed macromolecular structural information being available on the target so close to the beginning of the design effort. The X-ray molecular structure of two substrate-derived, peptidic inhibitors, MVT-101 (20, Ki = 0.78 jlM) and JG-36580 (21, K, = 0.24 nM) complexed with HIV 

Since the computational chemistry literature associated with HIV protease is so extensive, and since specialized reviews already exist in this area, this section focuses on only a few of the more recent examples of peptide mimetic 

Scientists at Agouron Pharmaceuticals designed replacements for the C-terminal Val-Val methyl ester of a known hydroxyethylene inhibitor of HIV-1 protease. 7 This effort began by overlaying an AMl -minimized structure of an unsubstituted model of the inhibitor (26) onto MVT-101 in its HIV 

Additional modeling studies, together with synthetic considerations, led to the design of the cyclic urea diol framework (27). Molecular modeling of this 

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Fitzsimmons, M. E., Collins, J. M., Selective biotransformation of the human immunodeficiency virus protease inhibitor saquinavir by human small-intestinal cytochrome P4503A4 potential contribution to high first-pass metabolism, Drug. Metab. Dispos. 1997, 25, 256-266. 

Crixivan inhibits an enzyme called HIV (human immunodeficiency virus) protease. 

Leonard, S., Van Schepdael, A., Ivanyi, T., Lazar, L, Rosier, J., Vanstockem, M., Vermeersch, H., and Hoogmartens, J. (2005). Development of a capillary electrophoretic method for the separation of diastereoisomers of a new human immunodeficiency virus protease inhibitor. Electrophoresis 26, 627-632. 

Chiba M, Hensleigh M, Nishime JA, Balani SK, Lin JH. Role of C5dochrome P450 3A4 in human metabolism of MK-639, a potent human immunodeficiency virus protease inhibitor. Drug Metab Dispos 1996 24(3) 307-314. 

Koudriakova T, latsimirskaia E, Utkin I, et al. Metabolism of the human immunodeficiency virus protease inhibitors indinavir and ritonavir by human intestinal microsomes and expressed cytochrome P4503A4/3A5 mechanism-based inactivation of cytochrome P4503A by ritonavir. Drug Metab Dispos 1998 26(6) 552-561. 

Reich SH, Melnick M, Davies JF, Appelt K, Lewis KK, Fuhry MA, Pino M, Trippe AJ, Nguyen D, Dawson H, Wu B-W, Musick L, Kosa M, Kahil D, Webber S, Gehlhaar DK, Andrada D, Shetty B. Protein structure-based design of potent, orally bioavailable, nonpeptide inhibitors of human immunodeficiency virus protease. Proc. Natl. Acad. Sci. 1995 92 3298-3302. 

Hsu A, Plattner JJ, Leonard JM, Norbeck DW. ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral availability in humans. Proc. Natl. Acad. Sci. USA. 1995 92 2484-2488. 

Furfine, E. S., Baker, C. T., Hale, M. R., Reynolds, D. J., Salisbury, J. A., Searle, A. D., Studenberg, S. D., Todd, D., Tung, R. D., and Spaltenstein, A. (2004). Preclinical pharmacology and pharmacokinetics of GW433908, a water-soluble prodrug of the human immunodeficiency virus protease inhibitor amprenavir. Antimicrob. Agents Chemother. 48 791-798. 

Since the discovery of cis-1 -amino-2-indanol as a ligand for human immunodeficiency virus protease inhibitors and the development of a practical industrial process for the synthesis of either ris-isomers in enantiopure form, the remarkable properties of the rigid indane platform have been used extensively in an ever-increasing number of asymmetric methodologies. In addition to the use of this amino alcohol as a chiral auxiliary and ligand for asymmetric synthesis, it has found application as a useful resolution agent. Applications include amines, carboxylic acids, and alcohols. 

FIGURE 24.1 Structure of human immunodeficiency virus protease (HIV-PR) inhibitor L-685,434 (2). 

Kohl NE, Emini EA, Schleif WA, Davis LJ, Heimbach JC, Dixon RA, et al. Active human immunodeficiency virus protease is required for viral infectivity. Proc. Natl. Acad. Sci. U.S.A. 1988 85(13) 4686-4690. 

Burger and his colleagues have illustrated an example of bridging different populations with PK/PD modeling to assess the dose adjustment need. They compared the PK/PD relationships of indinavir, a human immunodeficiency virus protease inhibitor, with or without ritonavir, in HIV-infected Thai patients to those in Caucasian patients, and recommended no dose adjustment despite the general lower body weight in the Thai population. ... 

Sadler BM, Gillotin C, Lou Y, Eron JJ, Lang W, Haubrich R, Stein DS. Pharmacokinetic study of human immunodeficiency virus protease inhibitors used in combination with amprenavir. Antimicrob Agents Chemother 2001 45(12) 3663-8. 

Gregoor PJ, van Gelder T, van der Ende ME, Ijzermans JN, Weimar W. Cyclosporine and triple-drug treatment with human immunodeficiency virus protease inhibitors. Transplantation 1999 68(8) 1210. 

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