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Designed, synthetically accessible bryostatin analogues potently induce activation of latent HIV reservoirs in vitro

Abstract

Bryostatin is a unique lead in the development of potentially transformative therapies for cancer, Alzheimer's disease and the eradication of HIV/AIDS. However, the clinical use of bryostatin has been hampered by its limited supply, difficulties in accessing clinically relevant derivatives, and side effects. Here, we address these problems through the step-economical syntheses of seven members of a new family of designed bryostatin analogues using a highly convergent Prins-macrocyclization strategy. We also demonstrate for the first time that such analogues effectively induce latent HIV activation in vitro with potencies similar to or better than bryostatin. Significantly, these analogues are up to 1,000-fold more potent in inducing latent HIV expression than prostratin, the current clinical candidate for latent virus induction. This study provides the first demonstration that designed, synthetically accessible bryostatin analogues could serve as superior candidates for the eradication of HIV/AIDS through induction of latent viral reservoirs in conjunction with current antiretroviral therapy.

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Figure 1
Figure 2: Synthesis of analogues 14 via Prins-driven macrocyclization.
Figure 3: Synthesis of analogues 57 via ozonolysis followed by Horner–Wadsworth–Emmons olefination.

References

  1. Fauci, A. S. et al. HIV vaccine research: the way forward. Science 321, 530–532 (2008).

    Article  CAS  Google Scholar 

  2. Davey, R. T. Jr et al. HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. Proc. Natl Acad. Sci. USA 96, 15109–15114 (1999).

    Article  CAS  Google Scholar 

  3. Carr, A. Toxicity of antiretroviral therapy and implications for drug development. Nature Rev. Drug Discov. 2, 624–634 (2003).

    Article  CAS  Google Scholar 

  4. Mills, E. J. et al. Adherence to HAART: a systematic review of developed and developing nation patient-reported barriers and facilitators. PLoS Med. 3, 2039–2064 (2006).

    Google Scholar 

  5. Bangsberg, D. R. et al. High levels of adherence do not prevent accumulation of HIV drug resistance mutations. AIDS 17, 1925–1932 (2003).

    Article  Google Scholar 

  6. Ruff, C. T. et al. Persistence of wild-type virus and lack of temporal structure in the latent reservoir for human immunodeficiency virus type 1 in pediatric patients with extensive antiretroviral exposure. J. Virol. 76, 9481–9492 (2002).

    Article  CAS  Google Scholar 

  7. Bailey, J. R. et al. Residual human immunodeficiency virus type 1 viremia in some patients on antiretroviral therapy is dominated by a small number of invariant clones rarely found in circulating CD4+ T cells. J. Virol. 80, 6441–6457 (2006).

    Article  CAS  Google Scholar 

  8. Dinoso, J. B. et al. Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. Proc. Natl Acad. Sci. USA 160, 9403–9408 (2009).

    Article  Google Scholar 

  9. Coiras, M., Lopez-Huertas, M. R., Perez-Olmeda, M. & Alcami, J. Understanding HIV-1 latency provides clues for the eradication of long-term reservoirs. Nature Rev. 7, 798–812 (2009).

    CAS  Google Scholar 

  10. Finzi, D. et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nature Med. 5, 512–517 (1999).

    Article  CAS  Google Scholar 

  11. Richman, D. D. et al. The challenge of finding a cure for HIV infection. Science 323, 1304–1307 (2009).

    Article  CAS  Google Scholar 

  12. Stellbrink, H-J. et al. Effects of interleukin-2 plus highly active antiretroviral therapy on HIV-1 replication and proviral DNA (COSMIC trial). AIDS 16, 1479–1487 (2002).

    Article  CAS  Google Scholar 

  13. Van Praag, R. M. E. et al. OKT3 and IL-2 treatment for purging of the latent HIV-1 reservoir in vivo results in selective long-lasting CD41 T cell depletion. J. Clin. Immunol. 21, 218–226 (2001).

    Article  CAS  Google Scholar 

  14. Kulkosky, J. et al. Prostratin: activation of latent HIV-1 expression suggests a potential inductive adjuvant therapy for HAART. Blood 98, 3006–3015 (2001).

    Article  CAS  Google Scholar 

  15. Korin, Y. D., Brooks, D. G., Brown, S., Korotzer, A. & Zack, J. A. Effects of prostratin on T-cell activation and human immunodeficiency virus latency. J. Virol. 76, 8118–8123 (2002).

    Article  CAS  Google Scholar 

  16. Brow, S. J. & Hezarah, M. Methods of administering prostratin and structural analogs thereof. US patent no. 2009126949 (2009).

  17. Wender, P. A., Kee, J-M. & Warrington, J. M. Practical synthesis of prostratin, DPP, and their analogs, adjuvant leads against latent HIV. Science 320, 649–652 (2008).

    Article  CAS  Google Scholar 

  18. Pettit, G. R. et al. Isolation and structure of bryostatin 1. J. Am. Chem. Soc. 104, 6846–6848 (1982).

    Article  CAS  Google Scholar 

  19. Kortmansky, J. & Schwartz, G. K. Bryostatin-1: a novel PKC inhibitor in clinical development. Cancer Invest. 21, 924–936 (2003).

    Article  CAS  Google Scholar 

  20. Hale, K. J., Hummersone, M. G., Manaviazar, S. & Frigerio, M. The chemistry and biology of the bryostatin antitumour macrolides. Nat. Prod. Rep. 19, 413–453 (2002).

    Article  CAS  Google Scholar 

  21. Etcheberrigaray, R. et al. Therapeutic effects of PKC activators in Alzheimer's disease transgenic mice. Proc. Natl Acad. Sci. USA 101, 11141–11146 (2004).

    Article  CAS  Google Scholar 

  22. Kinter, A. L., Poli, G., Maury, W., Folks, T. M. & Fauci, A. S. Direct and cytokine-mediated activation of protein kinase C induces human immunodeficiency virus expression in chronically infected promonocytic cells. J. Virol. 64, 4306–4312 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Quatsha, K. A., Rudolph, C., Marme, D., Schachtele, C. & May, W. S. Go 6976, a selective inhibitor of protein kinase C, is a potent antagonist of human immunodeficiency virus 1 induction from latent/low-level-producing reservoir cells in vitro. Proc. Natl Acad. Sci. USA 90, 4674–4676 (1993).

    Article  Google Scholar 

  24. Mehla, R. et al. Bryostatin modulates latent HIV-1 infection via PKC and AMPK signaling but inhibits acute infection in a receptor independent manner. PLoS One 5, e11160 (2010).

    Article  Google Scholar 

  25. Barr, P. M. et al. Phase II study of bryostatin 1 and vincristine for aggressive non-Hodgkin lymphoma relapsing after an autologous stem cell transplant. Am. J. Hematol. 84, 484–487 (2009).

    Article  CAS  Google Scholar 

  26. Schaufelberger, D. E. et al. The large-scale isolation of bryostatin 1 from Bugula neritina following current good manufacturing practices. J. Nat. Prod. 54, 1265–1270 (1991).

    Article  CAS  Google Scholar 

  27. Trindade-Silva, A. E., Lim-Fong, G. E., Sharp, K. H. & Haygood, M. G. Bryostatins: biological context and biotechnological prospects. Curr. Opin. Biotechnol. 21, 834–842 (2010).

    Article  CAS  Google Scholar 

  28. Kageyama, M. et al. Synthesis of bryostatin 7. J. Am. Chem. Soc. 112, 7407–7408 (1990).

    Article  CAS  Google Scholar 

  29. Evans, D. A. et al. Total synthesis of bryostatin 2. J. Am. Chem. Soc. 121, 7540–7552 (1999).

    Article  CAS  Google Scholar 

  30. Ohmori, K. et al. Total synthesis of bryostatin 3. Angew. Chem. Int. Ed. 39, 2290–2294 (2000).

    Article  CAS  Google Scholar 

  31. Trost, B. M. & Dong, G. Total synthesis of bryostatin 16 using atom-economical and chemoselective approaches. Nature 456, 485–488 (2008).

    Article  CAS  Google Scholar 

  32. Keck, G. E., Poudel, Y. B., Cummins, T. J., Rudra, A. & Covel, J. A. Total synthesis of bryostatin 1. J. Am. Chem. Soc. 133, 744–747 (2011).

    Article  CAS  Google Scholar 

  33. Wender, P. A. & Schrier, A. J. Total synthesis of bryostatin 9. J. Am. Chem. Soc. 133, 9228–9231 (2011).

    Article  CAS  Google Scholar 

  34. Lu, Y., Woo, S. & Krische, M. J. Total synthesis of bryostatin 7 via C–C bond-forming hydrogenation. J. Am. Chem. Soc. 133, 13876–13879 (2011).

    Article  CAS  Google Scholar 

  35. Wender, P. A. et al. Modeling of the bryostatins to the phorbol ester pharmacophore on protein kinase C. Proc. Natl Acad. Sci. USA 85, 7197–7201 (1988).

    Article  CAS  Google Scholar 

  36. Wender, P. A. in Drug Discovery Research: New Frontiers in the Post-Genomic Era (ed. Huang, Z.) Ch. 6 (Wiley-VCH, 2007).

  37. Wender, P. A., Loy, B. A. & Schrier, A. J. Translating nature's library: the bryostatins and function-oriented synthesis. Isr. J. Chem. 51, 453–472 (2011).

    Article  CAS  Google Scholar 

  38. Wender, P. A., Verma, V. A., Paxton, T. J. & Pillow, T. H. Function-oriented synthesis, step economy, and drug design. Acc. Chem. Res. 41, 40–49 (2008).

    Article  CAS  Google Scholar 

  39. Wender, P. A. et al. Synthesis of the first members of a new class of biologically active bryostatin analogues. J. Am. Chem. Soc. 120, 4534–4535 (1998).

    Article  CAS  Google Scholar 

  40. Wender, P. A. et al. The practical synthesis of a novel and highly potent analogue of bryostatin. J. Am. Chem. Soc. 124, 13648–13649 (2002).

    Article  CAS  Google Scholar 

  41. Wender, P. A., DeChristopher, B. A. & Schrier, A. J. Efficient synthetic access to a new family of highly potent bryostatin analogues via a Prins-driven macrocyclization strategy. J. Am. Chem. Soc. 130, 6658–6659 (2008).

    Article  CAS  Google Scholar 

  42. Wender, P. A. et al. Design, synthesis, and evaluation of potent bryostatin analogs that modulate PKC translocation selectivity. Proc. Natl Acad. Sci. USA 108, 6721–6726 (2011).

    Article  CAS  Google Scholar 

  43. Mackay, H. J. & Twelves, C. J. Targeting the protein kinase C family: are we there yet? Nature Rev. Cancer 7, 554–562 (2007).

    Article  CAS  Google Scholar 

  44. DeChristopher, B. A., Fan, A. C., Felsher, D. W. & Wender, P. A. ‘Picolog’, a synthetically-available bryostatin analog, inhibits growth of MYC-induced lymphoma in vivo. Oncotarget 3, 58–66 (2012).

    Article  Google Scholar 

  45. Khan, T. K., Nelson, T. J., Verma, V. A., Wender, P. A. & Alkon, D. L. A cellular model of Alzheimer's disease therapeutic efficacy: PKC activation reverses Aβ-induced biomarker abnormality on cultured fibroblasts. Neurobiol. Dis. 34, 332–339 (2009).

    Article  CAS  Google Scholar 

  46. Crane, E. A. & Scheidt, K. A. Prins-type macrocyclizations as an efficient ring-closing strategy in natural product synthesis. Angew. Chem. Int. Ed. 49, 8316–8326 (2010).

    Article  CAS  Google Scholar 

  47. Krasovskiy, A., Kopp, F. & Knochel, P. Soluble lanthanide salts (LnCl3·2LiCl) for the improved addition of organomagnesium reagents to carbonyl compounds. Angew. Chem. Int. Ed. 45, 497–500 (2006).

    Article  CAS  Google Scholar 

  48. Marsden, M. D. & Zack, J. A. Establishment and maintenance of HIV latency: model systems and opportunities for intervention. Future Virol. 5, 97–109 (2010).

    Article  CAS  Google Scholar 

  49. Jordan, A., Bisgrove, D. & Verdin, E. HIV reproducibly establishes a latent infection after acute infection in T cells in vitro. EMBO J. 22, 1868–1877 (2003).

    Article  CAS  Google Scholar 

  50. Williams, S. A. et al. Prostratin antagonizes HIV latency by activating NF-κB. J. Biol. Chem. 279, 42008–42017 (2004).

    Article  CAS  Google Scholar 

  51. Kovochich, M., Marsden, M. D. & Zack, J. A. Activation of latent HIV using drug-loaded nanoparticles. PLoS One 6, e18270 (2011).

    Article  CAS  Google Scholar 

  52. Brooks, D. G. et al. Molecular characterization, reactivation, and depletion of latent HIV. Immunity 19, 413–423 (2003).

    Article  CAS  Google Scholar 

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Acknowledgements

This research was supported by the National Institutes of Health (CA31845 to P.A.W., AI070010 to J.A.Z.) and the UCLA Center for AIDS Research (AI028697). Additional funding was provided by the ACS Division of Organic Chemistry Graduate Fellowship sponsored by Bristol-Myers Squibb, the Eli Lilly Organic Chemistry Graduate Fellowship, and the Stanford University Center for Molecular Analysis and Design.

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B.A.D., B.A.L., M.D.M., A.J.S., J.A.Z. and P.A.W. conceived and designed the experiments. B.A.D., B.A.L., M.D.M. and A.J.S. performed the experiments and analysed the data. B.A.L., M.D.M., A.J.S. and P.A.W. co-wrote the paper. All authors commented on the manuscript.

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Correspondence to Jerome A. Zack or Paul A. Wender.

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DeChristopher, B., Loy, B., Marsden, M. et al. Designed, synthetically accessible bryostatin analogues potently induce activation of latent HIV reservoirs in vitro. Nature Chem 4, 705–710 (2012). https://doi.org/10.1038/nchem.1395

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