Bryostatins: biological context and biotechnological prospects

Abstract

Summary of recent advances Bryostatins are a family of protein kinase C modulators that have potential applications in biomedicine. Found in miniscule quantities in a small marine invertebrate, lack of supply has hampered their development. In recent years, bryostatins have been shown to have potent bioactivity in the central nervous system, an uncultivated marine bacterial symbiont has been shown to be the likely natural source of the bryostatins, the bryostatin biosynthetic genes have been identified and characterized, and bryostatin analogues with promising biological activity have been developed and tested. Challenges in development of bryostatins for biomedical and biotechnological application include the cultivation of the bacterial symbiont and heterologous expression of bryostatin biosynthesis genes. Continued exploration of the biology and the symbiotic origin of the bryostatins presents promising opportunities for discovery of additional bryostatins, and new functions for bryostatins.

Recherche de substances naturelles à activité thérapeutique (2)

“…Par la suite, une vingtaine de nouvelles bryostatines seront découvertes chez B. neritina récolté dans divers sites. [11] La première synthèse totale de la bryostatine 1, en 58 étapes, est pré-sentée en 2011 par G.E. Keck [12].…”

“…La bryostatine 1, en association avec le paclitaxel 2 , accroît la réponse thérapeutique chez des patients atteints d'adénocarcinome gastrique ou gastro-oesophagique avancé non traité. Cependant, des études approfondies seront nécessaires pour réduire le seul effet secondaire répertorié, les myalgies, avant d'exploiter complètement le potentiel thérapeutique de la bryostatine 1 [11]. La bryostatine 1 a également des effets antidépresseurs et activateurs de la cognition probablement via son action sur les PKC, impliquées dans la synthèse des protéines nécessaires à la mémoire de long terme.…”

Marine natural products: Bryostatins in preclinical and clinical studies

“…Nevertheless, interestingly, based on striking positive results produced by bryostatin in central nervous system models in rodents, a human Alzheimer's disease phase II clinical trial has been initiated with bryostatin-1 (Trindade-Silva et al, 2010). Most recently, bryostatin has been proposed as a possible therapy for human immunodeficiency virus (HIV) (Mehla et al, 2010).…”

“…Although current antiviral therapy is effective against HIV, the disease cannot be cured because of latent viruses persisting in resting cells. On the basis of in vitro studies, bryostatins may be effective in activating latent viruses so they can be purged from cellular reservoirs, exposed to antiviral therapy, and eliminated (Trindade-Silva et al, 2010).…”

“…Basically, most, but not all, of bryostatins' pharmacological effects are attributed to its interaction with the diacylglycerol (DAG) binding site of the C-1, C-19 and C-26 regulatory domain of PKC (Trindade-Silva et al, 2010). PKC exists in 10 isoforms, variously regulated by DAG, Ca 2þ and phospholipid, and it is likely that when bryostatin-1 binds to the cysteine-rich domains of PKC, similar changes occur, though specific differences may well occur with different PKCs (Newman, 2012).…”