Michael J. Bowman, Simon Byrne, Jean Chmielewski Chemistry & Biology

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Presentation transcript:

Switching between Allosteric and Dimerization Inhibition of HIV-1 Protease Michael J. Bowman, Simon Byrne, Jean Chmielewski Chemistry & Biology Volume 12, Issue 4, Pages 439-444 (April 2005) DOI: 10.1016/j.chembiol.2005.02.004 Copyright © 2005 Elsevier Ltd Terms and Conditions

Figure 1 Structure of Compounds 1–3 See text for details. Chemistry & Biology 2005 12, 439-444DOI: (10.1016/j.chembiol.2005.02.004) Copyright © 2005 Elsevier Ltd Terms and Conditions

Figure 2 Inhibition Analysis of Compound 3 (A) Lineweaver-Burk double reciprocal plot for inhibitor 3 with 25 nM HIV-1 PR. ●, uninhibited HIV PR; ○, 6 μM 3. (B) Zhang-Poorman analysis for 3 (5–25 nM HIV-1 PR, 25 μM substrate). ○, uninhibited HIV PR; ◊, 6 μM 3. Error bars were obtained from an average of two trials. Chemistry & Biology 2005 12, 439-444DOI: (10.1016/j.chembiol.2005.02.004) Copyright © 2005 Elsevier Ltd Terms and Conditions

Figure 3 Yonetani-Theorell Inhibition Analysis of Compound 3 (A) Yonetani-Theorell plot of v/vi versus concentration of compound 3 in systems containing constant acetyl-pepstatin concentrations. ●, 0 nM acetyl-pepstatin; ○, 72 nM acetyl-pepstatin; ▾, 109 nM acetyl-pepstatin; ▿, 145.5 nM acetyl-pepstatin. (25 nM HIV-1 PR, 12.5 μM substrate). (B) Yonetani-Theorell plot of v/vi versus concentration of acetyl-pepstatin in systems containing constant concentrations of compound 3. ●, 0 μM compound 3; ○, 4 μM compound 3; ▽, 6 μM compound 3; ▾, 8 μM compound 3 (25 nM HIV-1 PR, 12.5 μM substrate). Error bars were obtained from an average of two trials. Chemistry & Biology 2005 12, 439-444DOI: (10.1016/j.chembiol.2005.02.004) Copyright © 2005 Elsevier Ltd Terms and Conditions

Figure 4 Inhibition Analysis of Compounds 4–10 (A) Structural data for compounds 4–10. (B) Zhang-Poorman assay of compounds 7, 8, and 10. ○, uninhibited HIV-1 PR; ♢, 1.6 μM compound 7; ▵, 2.9 μM compound 8; ▿, 1.4 μM compound 10 (3–36 nM HIV-1 PR, 25 μM substrate). (C) Kinetic data for compounds 4–10. Error bars were obtained from an average of two trials. Chemistry & Biology 2005 12, 439-444DOI: (10.1016/j.chembiol.2005.02.004) Copyright © 2005 Elsevier Ltd Terms and Conditions

Figure 5 Inhibition Analysis of Compounds 11 and 12 (A) Structural data for compounds 11 and 12. (B) Zhang-Poorman assay of compounds 11 and 12. ○, uninhibited HIV-1 PR; ▵, 660 nM compound 11; ▿ 500 nM compound 12 (3–36 nM HIV-1 PR, 25 μM substrate). (C) Kinetic data for compounds 11 and 12. Error bars were obtained from an average of two trials. Chemistry & Biology 2005 12, 439-444DOI: (10.1016/j.chembiol.2005.02.004) Copyright © 2005 Elsevier Ltd Terms and Conditions

Figure 6 A model of the biphenylether portion of compound 12 bound to the protease monomer. See text for details. Chemistry & Biology 2005 12, 439-444DOI: (10.1016/j.chembiol.2005.02.004) Copyright © 2005 Elsevier Ltd Terms and Conditions