期刊
NATURE CHEMISTRY
卷 4, 期 9, 页码 705-710出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEM.1395
关键词
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资金
- National Institutes of Health [CA31845, AI070010]
- UCLA Center for AIDS Research [AI028697]
- ACS Division of Organic Chemistry Graduate Fellowship
- Bristol-Myers Squibb
- Eli Lilly Organic Chemistry Graduate Fellowship
- Stanford University Center for Molecular Analysis and Design
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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