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XVIII International AIDS Conference

XVIII International AIDS Conference. Novel HIV-1 Protease Inhibitors Containing bis -Tetrahydrofuran or a Novel Polycyclic Ligand, Pyranofuran. Kazuhiko Ide 1 , M. Aoki 1,2 , Y. Koh 1 , M. Amano 1 ,

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XVIII International AIDS Conference

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  1. XVIII International AIDS Conference Novel HIV-1 Protease Inhibitors Containing bis-Tetrahydrofuran or a Novel Polycyclic Ligand, Pyranofuran Kazuhiko Ide1, M. Aoki1,2, Y. Koh1, M. Amano1, S. Kulkarni3, D.D. Anderson3, B. Chapsal3, R. Yedidi4, D. Das4, A.K. Ghosh3, and H. Mitsuya1,4 1Depts of Hematology and Infectious Diseases, Kumamoto Univ; 2Kumamoto Health Science Univ; 3Depts. of Chem & Med Chem, Purdue Univ; 4Experimental Retrovirology Section, NCI, NIH.

  2. Background HAART made a major impact on the morbidity of HIV-1-infected individuals and significantly extended their survival. The emergence of multi-drug-resistant viruses (HIV-1MDR) is still one of the major concerns. Continuous efforts are required to develop more potent and safer therapeutics with high genetic barrier.

  3. Darunavir bis-THF bis-tetrahydrofuran Koh, Ghosh & Mitsuya. Antimicrob Agents Chemother 47:3123-3129, 2003 DRV possesses a dual antiviral activity, i.e., protease inhibition and protease dimerization inhibition. Koh & Mitsuya. J Biol Chem. 282:28709-20, 2007 The presence of bis-THF is important for the antiviral activity of DRV.

  4. GRL-0878 GRL-0888 6 5 5 6 Major Isomer Minor Isomer ( Cis ) ( Trans ) bis-THF bis-THF GRL-1388 GRL-1398 polycyclic ligand polycyclic ligand (pyranofuran) (pyranofuran)

  5. Four New Compounds Are Comparably or More Potent against HIV Compared to DRV *Selectivity index = CC50 / EC50

  6. GRL-1398 Is More Potent against a Wide Spectrum of HIVMDR Isolates than DRV (fold change), blue：5-10 times, red：>10 times

  7. GRL-1398 Is Active against DRV-resistant HIV Variants (Fold-change)

  8. Intermolecular FRET (Fluorescence Resonance Energy Transfer)-based FRET-HIV-1 Expression System Apa Spacer 99 AA 238 AA F/P RT Cyan Fluorescent Protein PR AAAAA pHIV-1NL43sma PR Yellow Fluorescent Protein RT AAAAA Protease or polyprotein Monomer Protease or Polyprotein Dimerization YFP Protease or polyprotein Monomer If CFPA/B ratios are < 1.0, there is no FRET or dimerization Monomer-monomer Interactions CFP FRET 1 - 10 nm

  9. GRL-1388 and -1398 have PDI activity p = 0.0001 p = 0.0005 1.5 p = 0.15 Dimerization＋ p <0.0001 1.4 p = 0.07 1.3 1.2 1.1 CFPA/B ratio 1.12 1.10 1.0 1.02 0.9 0.92 0.96 0.8 0.7 0.88 0.86 0.85 0.83 Dimerization－ 0.81 0.6 0.5 1 10 20 1 10 20 1 10 20 (μM) None GRL-1388 GRL-1398 DRV

  10. A28S/M46I Confer Resistance to GRL-1398 on HIVNL4-3 L10F A28S M46I L10F V32I L33F M46L I54M A71V APV L10F V32I M46L V82I DRV GRL-1388 GRL-1398 L10F A28S M46I L10F Cells used : MT4 Weeks

  11. GRL-1398 Resists against Emergence of HIVDRVR with a Mixture of 8 HIV-1MDR Isolates DRV GRL-1388 L10I L33I M36I M46I L63P A71V V82A L90M GRL-1398 Weeks Cells used : MT4

  12. GRL-1398 Has Tight Interactions with PR VAL82 ASP29’ ASP30’ ILE84 ILE50’ GLY27’ H2O ALA28’ VAL32 ASP25 GLY49 GLY48 ILE84’ ILE47 PRO81’ ASP30 ALA28 ASP29 VAL82’

  13. Summary GRL-1388 and -1398, containing a novel structure-based designed ligand, were comparably or more potent compared to DRV. Although GRL-1398 had moderate PDI activity as compared to DRV, GRL-1398 exhibited more potent anti-HIV activity against DRV- resistant HIV variants.

  14. Conclusions GRL-1398 has activity against protease’s enzymatic activity and dimerization activity with high genetic barrier. It is warranted that the compounds, especially GRL-1398, be further studied as potential therapeutics for HIVwt and HIV-1MDR infection.

  15. Thank you for your attention

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