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

Nat Chem. 2012 Sep;4(9):705-10. doi: 10.1038/nchem.1395. Epub 2012 Jul 15.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology
  • Bryostatins / chemical synthesis
  • Bryostatins / chemistry*
  • Bryostatins / pharmacology*
  • Cell Line
  • Chemical Engineering
  • Drug Design
  • HIV / physiology
  • Humans
  • Phorbol Esters / chemistry
  • Phorbol Esters / pharmacology
  • Protein Kinase C / metabolism
  • Rats
  • Virus Activation / drug effects

Substances

  • Anti-HIV Agents
  • Bryostatins
  • Phorbol Esters
  • prostratin
  • Protein Kinase C

Associated data

  • PubChem-Substance/136329170
  • PubChem-Substance/136329171
  • PubChem-Substance/136329172
  • PubChem-Substance/136329173
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  • PubChem-Substance/136329205