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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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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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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DOI: https://doi.org/10.1038/nchem.1395
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