Human immunodeficiency vims protease

Lin JH, Chiba M, Balani SK, et al. Species differences in the pharmacokinetics and metabolism of indinavir, a potent human immunodeficiency vims protease inhibitor. Dmg Metab Dispos 1996 24(10) 1111-1120. 

Cassone A, De Bemardis F, Torosantucci A, Tacconelli E, Tumbarello M, Cauda R In vitro and in vivo anticandidal activity of human immunodeficiency vims protease inhibitors. J. Infect Dis 1999 180 448 53. 

Changes in human immunodeficiency vims type 1 Gag at positions 1449 and P453 are linked to I50V protease mutants in vivo and cause reduction of sensitivity to amprenavir and improved viral fitness in vitro. J Virol 76 7398-7406... 

Mammano F, Petit C, Clavel F (1998) Resistance-associated loss of viral fitness in human immunodeficiency vims type 1 phenotypic analysis of protease and gag coevolution in protease inhibitor-treated patients. J Virol 72 7632-7637... 

Waller, C.L., Oprea, T.I., Giolitti, A., and Marshall, G.R. Three-dimensional QSAR of human immunodeficiency vims (1) protease inhibitors. 

Ido, E., Kezdy, F.J., Han, H., and Tang, J. (1991) Kinetic studies of human immunodeficiency vims type I protease and its active-site hydrogen bond mutant A28S.T. Biol. Chem., 226, 24359-24366. 

Retroviruses encode a protease (PR) responsible for cleaving polyprotein precursors, and such processing is essential for proper virion assembly and maturation. Based on the presence of a sequence Asp-Ser/Thr-Gly in the active sites of retroviral proteases (1) and their inhibition in vitro by pepstatin (2-7), these enzymes have been classified as members of the aspartic protease family. Crystal structures have been determined for the proteases from Rous sarcoma virus (RSV PR) (8), from two variants and several mutants of the human immunodeficiency vims (HIV PR) (9-11), from feline immunodeficiency virus (FIV PR) (12) and from equine infectious anemia vims (EIAV PR) (13). Aspartic proteases contain a single active site which includes two aspartates. In apoenzymes, the two catalytic Asp residues from the active site triad have been found to be in hydrogen bond contact with a water molecule (10). Mutations of the active site Asp25 in HIV-1 PR into Asn (14,15), Thr (3) or Ala (4,16,17) led to an inactive enzyme. Similarly, the RSV PR was inactivated by mutation of its active site Asp to He (18). 

In recent years, varions dmgs have been developed for the treatment of the human immunodeficiency vims (HIV) infection. The two most important compound classes are the HIV selective protease inhibitors, nucleoside reverse transcriptase inhibitors (NRTI), and the non-nucleoside reverse transcriptase inhibitors (tiNRTI). Methods developed for TDM of these compounds are discussed here. TDM is required because of a high inter- and intra-individual variability. 

Inhibition of human immunodeficiency vims type 1 reverse transcriptase by nucleosides such as AZT, DDC, DDI, D4T, and 3TC is a proven therapy for delaying the progression of AIDS. However, the rapid viral mutation to resistant strains requires the development of new therapeutic agents.The recent developments of both protease inhibitors and nonnucleoside reverse transcriptase inhibitors offer hope of effective treatment, especially when coadministered. " Efavirenz 290 is a nonnucleoside reverse transcriptase inhibitor that shows high potency against a variety of HIV-1 mutant strains. 

TC, lamivudine ABC, abacavir APV, amprenavir AST, aspartate aminotransferase ALT, alanine aminotransferase ATV, atazanavir CBC, complete blood cell count D/C, discontinue ddl, didano-sine d4T, stavudine EFV, efavirenz FTC, emtricitabine P1BV, hepatitis B virus F1CV, hepatitis C vims HIV, human immunodeficiency virus IDV, indinavir IV, intravenous LFT, liver function tests LPV/r, lopinavir + ritonavir NNRTI, nonnucleoside reverse transcriptase inhibitor NRTI, nucleoside reverse transcriptase inhibitor NVP, nevirapine PI, protease inhibitor PT, prothrombin time T.bili, total bilirubin TDF, tenofovir disoproxiI fumarate TPV, tipranavir ULN, upper limit of normal ZDV, zidovudine. 

Feh6r A, Boross P, Sperka T, Miklossy G, Kadas J, Bagossi P, Oroszlan S, Weber IT, T6zs6r J. Characterization of the murine leukemia vims protease and its comparison with the human immunodeficiency virus type 1 protease. J Gen Virol. 2006 87 1321-30. 

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