Bryostatin 1

We report that the addition of an host paracaspase MALT1 inhibitor, MI-2, to HIV latently infected ACH-2, Jurkat E4, and J-LAT cells accelerated cell death in the presence of cell stimuli or the protein kinase C agonist, bryostatin 1. MI-2-mediated cell death correlated with the induction of the cellular RNase MCPIP1 and requires the presence of viral component(s). Altogether, the combination of MI-2 and bryostatin 1 displays selective killing of HIV latently infected CD4(+) T cells.

Bryostatin-1 is a marine natural product that has demonstrated medicinal activity in pre-clinical and clinical trials for the treatment of cancer, Alzheimer's disease, effects of stroke, and HIV. In this study, iron-bryostatin-1 was obtained using a pharmaceutical aquaculture technique developed by our lab that cultivates marine bacteria for marine natural product extraction. Analytical measurements 1H and 13C NMR, mass spectrometry, and flame atomic absorption were utilized to confirm the presence of an iron-bryostatin-1 complex. The iron-bryostatin-1 complex produced was then tested against the National Cancer Institute's 60 cell line panel. Adding iron to bryostatin-1 lowered the anti-cancer efficacy of the compound.

Fragile X syndrome (FXS) is characterized by synaptic immaturity, cognitive impairment, and behavioral changes. The disorder is caused by transcriptional shutdown in neurons of thefragile X mental retardation 1gene product, fragile X mental retardation protein. Fragile X mental retardation protein is a repressor of dendritic mRNA translation and its silencing leads to dysregulation of synaptically driven protein synthesis and impairments of intellect, cognition, and behavior, and FXS is a disorder that currently has no effective therapeutics. Here, young fragile X mice were treated with chronic bryostatin-1, a relatively selective protein kinase Cεactivator, which induces synaptogenesis and synaptic maturation/repair. Chronic treatment with bryostatin-1 rescues young fragile X mice from the disorder phenotypes, including normalization of most FXS abnormalities in 1) hippocampal brain-derived neurotrophic factor expression, 2) postsynaptic density-95 levels, 3) transformation of immature dendritic spines to mature synapses, 4) densities of the presynaptic and postsynaptic membranes, and 5) spatial learning and memory.

OBJECTIVE: The protein kinase C-(PKC) agonist bryostatin-1 has shown significant ex vivo potency to revert HIV-1 latency, compared to other latency reversing agents-(LRA). The safety of this candidate LRA remains to be proven in treated HIV-1 infected-patients.