Targeting HIV-1 protease: a test of drug-design methodologies.

The proteinase of the human immunodeficiency virus (HIV-1 protease) is an obvious example of a receptor for which drug design methodologies have been successfully applied. In this article, Michael West and David Fairlie outline the specific progress made to date towards the rational design of protease inhibitors as anti-HIV drugs, and compare their pharmacological profiles. The rationale employed in designing protease inhibitors illustrates evolving trends in drug design, problems in comparing assay data, and obstacles to developing enzyme inhibitors into drugs.

[1]  M. Jaskólski,et al.  Conserved folding in retroviral proteases: crystal structure of a synthetic HIV-1 protease. , 1989, Science.

[2]  M. Hirsch,et al.  Human immunodeficiency virus type 1 (HIV-1) inhibitory interactions between protease inhibitor Ro 31-8959 and zidovudine, 2',3'-dideoxycytidine, or recombinant interferon-alpha A against zidovudine-sensitive or -resistant HIV-1 in vitro. , 1992, The Journal of infectious diseases.

[3]  T L Blundell,et al.  The 3-D structure of HIV-1 proteinase and the design of antiviral agents for the treatment of AIDS. , 1990, Trends in biochemical sciences.

[4]  PatrickY.-S. Lam,et al.  Rational design of potent, bioavailable, nonpeptide cyclic ureas as HIV protease inhibitors. , 1994, Science.

[5]  S. Vasavanonda,et al.  Antiviral and pharmacokinetic properties of C2 symmetric inhibitors of the human immunodeficiency virus type 1 protease , 1991, Antimicrobial Agents and Chemotherapy.

[6]  Elaine C. Meng,et al.  Structure of a non-peptide inhibitor complexed with HIV-1 protease. Developing a cycle of structure-based drug design. , 1997 .

[7]  Martin J. Stoermer,et al.  Flavones are inhibitors of HIV-1 proteinase. , 1992, Biochemical and biophysical research communications.

[8]  J. Urban,et al.  Specificity mapping of HIV-1 protease by reduced bond inhibitors. , 1993, Archives of biochemistry and biophysics.

[9]  D. Egan,et al.  Design of a well-absorbed renin inhibitor. , 1991, Journal of medicinal chemistry.

[10]  New hydroxyethylamine HIV protease inhibitors that suppress viral replication. , 1992, Journal of medicinal chemistry.

[11]  T. Klimkait,et al.  CGP 53437, an orally bioavailable inhibitor of human immunodeficiency virus type 1 protease with potent antiviral activity , 1993, Antimicrobial Agents and Chemotherapy.

[12]  P. Darke,et al.  HIV-1 protease inhibitors based on hydroxyethylene dipeptide isosteres: an investigation into the role of the P1' side chain on structure-activity. , 1992, Journal of medicinal chemistry.

[13]  D. Fairlie,et al.  Non-peptidic anti-AIDS agents: inhibition of HIV-1 proteinase by disulfonates. , 1992, Biochemical and biophysical research communications.

[14]  A. Wlodawer,et al.  Different requirements for productive interaction between the active site of HIV-1 proteinase and substrates containing -hydrophobic*hydrophobic- or -aromatic*pro- cleavage sites. , 1992, Biochemistry.

[15]  A Wlodawer,et al.  Structure of complex of synthetic HIV-1 protease with a substrate-based inhibitor at 2.3 A resolution. , 1989, Science.

[16]  D. Norbeck,et al.  Design, activity, and 2.8 A crystal structure of a C2 symmetric inhibitor complexed to HIV-1 protease. , 1990, Science.

[17]  J M Blaney,et al.  Molecular modeling software and methods for medicinal chemistry. , 1990, Journal of medicinal chemistry.

[18]  A. Wlodawer,et al.  Structure-based inhibitors of HIV-1 protease. , 1993, Annual review of biochemistry.

[19]  D. Lambert,et al.  Human immunodeficiency virus type 1 protease inhibitors irreversibly block infectivity of purified virions from chronically infected cells , 1992, Antimicrobial Agents and Chemotherapy.

[20]  C. Humblet,et al.  A novel nonpeptide HIV-1 protease inhibitor: elucidation of the binding mode and its application in the design of related analogs. , 1994, Journal of medicinal chemistry.

[21]  I B Duncan,et al.  Rational design of peptide-based HIV proteinase inhibitors. , 1990, Science.

[22]  R A Mueller,et al.  Discovery of a novel class of potent HIV-1 protease inhibitors containing the (R)-(hydroxyethyl)urea isostere. , 1993, Journal of medicinal chemistry.

[23]  P. Darke,et al.  A series of potent HIV-1 protease inhibitors containing a hydroxyethyl secondary amine transition state isostere: synthesis, enzyme inhibition, and antiviral activity. , 1992, Journal of medicinal chemistry.

[24]  Y. Wong,et al.  A pharmacokinetic evaluation of HIV protease inhibitors, cyclic ureas, in rats and dogs , 1994, Biopharmaceutics & drug disposition.

[25]  S. Gulnik,et al.  In vitro anti-human immunodeficiency virus (HIV) activities of transition state mimetic HIV protease inhibitors containing allophenylnorstatine , 1993, Antimicrobial Agents and Chemotherapy.

[26]  M. Katharine Holloway,et al.  X-Ray Crystal Structure of the HIV Protease Complex with L-700,417, an Inhibitor with Pseudo C2 Symmetry , 1991 .

[27]  M. Kuroda,et al.  Generation and characterization of a human immunodeficiency virus type 1 (HIV-1) mutant resistant to an HIV-1 protease inhibitor , 1994, Journal of virology.

[28]  G R Marshall,et al.  Hydroxyethylamine analogues of the p17/p24 substrate cleavage site are tight-binding inhibitors of HIV protease. , 1990, Journal of medicinal chemistry.

[29]  K D Watenpaugh,et al.  Structure-based design of HIV protease inhibitors: 4-hydroxycoumarins and 4-hydroxy-2-pyrones as non-peptidic inhibitors. , 1994, Journal of medicinal chemistry.

[30]  J. Bilello,et al.  Preclinical evaluation of antiviral activity and toxicity of Abbott A77003, an inhibitor of the human immunodeficiency virus type 1 protease , 1993, Antimicrobial Agents and Chemotherapy.

[31]  A. Wlodawer,et al.  The complexities of AIDS : an assessment of the HIV protease as a therapeutic target , 1991 .

[32]  T. Shepherd,et al.  D-amino acids as novel P2/P3 ligands for inhibitors of HIV-1 protease , 1994 .