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

• Published in: Nature chemistry Vol. 4; no. 9; pp. 705 - 710
• Main Authors: DeChristopher, Brian A., Loy, Brian A., Marsden, Matthew D., Schrier, Adam J., Zack, Jerome A., Wender, Paul A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2012; Nature Publishing Group
• Subjects: 639/638/309; 639/638/549; 692/699/255/1901; Acquired immune deficiency syndrome; AIDS; Alzheimer's disease; Analytical Chemistry; Animals; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Antiretroviral agents; Biochemistry; Bryostatins - chemical synthesis; Bryostatins - chemistry; Bryostatins - pharmacology; Cell Line; Chemical Engineering; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Drug Design; Drug therapy; HIV; HIV - physiology; Human immunodeficiency virus; Humans; Inorganic Chemistry; Kinases; Organic Chemistry; Phorbol Esters - chemistry; Phorbol Esters - pharmacology; Physical Chemistry; Protein Kinase C - metabolism; Rats; Side effects; Virus Activation - drug effects; Los Angeles California; United States > US; California
• ISSN: 1755-4330; 1755-4349
• DOI: 10.1038/nchem.1395

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. Simplified bryostatin analogues are shown to potently induce latent HIV expression in vitro . These analogues display comparable or better potency when compared with bryostatin. Moreover, they are up to 1,000-fold more potent in inducing latent HIV expression than prostratin, the current lead preclinical candidate.