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Translating Nature's Library Yields Drug Leads for Aids, Cancer, Alzheimer's Disease
Myriam
Posted: Tuesday, September 10, 2013 1:08 AM
Joined: 12/6/2011
Posts: 3326


An ingredient in a medicinal tea brewed from tree bark by tribal healers on the South Pacific island of Samoa -- studied by scientists over the last 25 years -- is showing significant promise as a drug lead in the long-sought goal of eliminating the AIDS virus from its sanctuaries in the body and thus eradicating the disease, a scientist said. 


Speaking at the 246th National Meeting & Exhibition of the American Chemical Society (ACS), Paul A. Wender, Ph.D., described efficient new ways of making prostratin and related leads, as well as other drug candidates first discovered in sea creatures, that appear even more effective for AIDS and have applications for Alzheimer's disease and cancer. 

 

In his presentation, Wender focused on fundamentally new approaches to some of the most serious unmet health challenges of our time. He is with Stanford University. They include the eradication of AIDS, developing medicines that stop the progression of Alzheimer's disease and treating resistant cancer -- the major cause of chemotherapy failure for most cancers. 

 

Wender leads a scientific team at Stanford University that first developed a way to make the tea ingredient, prostratin, in large amounts from readily available ingredients. He described how that initial synthesis broke down a major barrier to probing prostratin's antiviral effects. Until then, scientists had to extract prostratin from the bark of the Samoan mamala tree, and only tiny and variable amounts were so obtained. Samoa is where another scientist, Paul Cox, in 1987 heard a native healer praise mamala bark tea as a remedy for viral hepatitis. It led scientists at the National Cancer Institute to analyze the bark and identify prostratin as a key ingredient. Wender's synthesis of prostratin opened the door to research on the substance and enabled his team to change prostratin's architecture. 

 

"We now have made synthetic variants of prostratin, called analogs, that are 100 times more potent than the natural product," Wender said. "That's part of the basis for our approach to advancing potentially transformative treatments for AIDS, Alzheimer's disease and resistant cancer. The mamala tree did not start making prostratin millions of years ago to treat a disease that appeared in the 20th century. The same is true for other substances that occur naturally in plants and animals. But we now have the tools to read nature's library and use the lessons learned there to design, make and study new molecules that address unmet medical needs. This "function-oriented" approach seeks to identify useful parts of molecules and then, based on this knowledge, to design new and more readily synthesized molecules that work better or work in totally new ways. This is a well-validated strategy, perhaps best exemplified by the emergence of modern aviation from knowledge of how birds fly." 

 

Those new versions of prostratin show promise in laboratory tests for both preventing HIV from infecting human cells and awakening dormant HIV viruses that are hiding inside human latently infected cells. Latent HIV cell reservoirs are untouchable by today's antiviral medicines. Antiviral medicines reduce active virus levels in patients' blood and keep patients healthy. But when patients stop the medication, the hibernating HIV in reservoirs awakens to resupply active virus. Prostratin flushes HIV out of its cellular sanctuaries so that antiviral drugs can attack and hopefully eradicate the HIV from the body. In essence, if one wants to eliminate a weed, one needs to get rid of its roots. 

 

Wender's group used those same "function-oriented" approaches in the design and synthesis of analogs of bryostatin, a substance that occurs naturally in sea creatures called bryozoans. 

 

"Bryostatin has shown great promise in laboratory experiments as the basis for development of potentially transformative medicines for cancer, Alzheimer's disease and the eradication of HIV/AIDS," Wender said. "However, its limited supply from natural sources has slowed research, and as with prostratin, it was not evolved in nature for modern therapeutic use. We have overcome both the supply and performance barriers by designing simpler and thus more readily synthesized analogs of bryostatin -- over 100 of them so far. When tested in various assays related to HIV/AIDS eradication, these analogs are up to 1,000-fold more potent in flushing HIV out of its hiding places than prostratin. Much needs to be done, but we are on a promising trajectory." 

 

Wender's group is working with colleagues at the National Institute of Allergy and Infectious Diseases, the UCLA Center for AIDS Research and the Collaboratory of AIDS Researchers for Eradication to conduct further studies on the analogs. The AIDS Research Alliance, an independent not-for-profit research organization, is advancing prostratin toward clinical trials. 

 

The research team is currently also focusing on bryostatin and designed analogs for their potential use in boosting memory in Alzheimer's patients. The compound is known to improve learning and memory in laboratory rats. It appears to cause formation of new connections in the brain that are associated with learning and memory. Wender noted that bryostatin and its analogs may also have benefits for people who have had strokes or other conditions in which learning and memory are impaired.  


onward
Posted: Tuesday, September 10, 2013 9:53 AM
Joined: 12/20/2011
Posts: 217


Myriam wrote:

...bryostatin, a substance that occurs naturally in sea creatures called bryozoans. 

 

"Bryostatin has shown great promise in laboratory experiments as the basis for development of potentially transformative medicines for ... Alzheimer's disease ... We have overcome both the supply and performance barriers by designing simpler and thus more readily synthesized analogs of bryostatin -- over 100 of them so far... 

 

The research team is currently also focusing on bryostatin and designed analogs for their potential use in boosting memory in Alzheimer's patients. The compound is known to improve learning and memory in laboratory rats. It appears to cause formation of new connections in the brain that are associated with learning and memory... 

 

____________________________________________ 

 

 

 

Myriam, thanks for posting. 

 

According to Wikipedia, "Currently bryostatin 1 is in clinical trial phase II for the treatment against Alzheimer's disease."

 

Here's info on the clinical trial:

 

Clinical Trials

 

Bryostatin – Phase II Clinical Testing of a non-toxic PKC Activator

The Food and Drug Administration (FDA) has given Blanchette Rockefeller Neurosciences Institute (BRNI) permission to conduct Phase II clinical trials of Bryostatin for the treatment of Alzheimer’s disease patients. The drug showed pre-clinical efficacy to not only treat Alzheimer’s disease symptoms, but also its underlying causes.
Bryostatin was originally created as an anti-cancer chemotherapy. When BRNI scientists extensively tested PKC activators against Alzheimer’s disease models, they discovered the drug’s hidden potential to stop Alzheimer’s disease. Over the past six years, the drug has shown remarkable possibilities. In preclinical testing, BRNI scientists experimented with Bryostatin on three species of Alzheimer’s disease transgenic mice, each species based on different human Alzheimer’s disease genes. The test results revealed that Bryostatin, and a related class of drugs discovered at BRNI, can reduce the toxic Alzheimer’s disease protein A Beta and the deposits of A Beta called amyloid plaques, restore lost synapses, and protect against the loss of memory functions. In related preclinical testing, Bryostatin has been shown to enhance and restore memory by rewiring connections in the brain previously destroyed by stroke, head trauma, or aging itself.

The Phase II trials will test these preclinical findings on human Alzheimer’s disease patients as well as controls, along with Bryostatin’s effects on molecular targets in the human body, such as the signaling enzyme PKC. The drug’s side effects will also be carefully monitored using low doses that were previously found to be generally benign in human cancer patients.
 

 

 

New Compounds for Clinical Testing  

  

Based on a large body of basic research on animal models as well as the potent and specific efficacy of Bryostatin for AD models, BRNI scientists synthesized an entirely new class of PKC Activators that activate the PKC enzyme at a different molecular site. These new drugs show highly specific and potent activation of one specific form of PKC know as PKC epsilon.  It is this isozyme that most directly controls synaptogenesis as well as protects against the toxic protein, A Beta, of AD.  These PKC epsilon activators are metabolized to substances that are already present in the diet but that lack the PKC activating capacity.  However, as metabolites they are non-toxic and thus support the lack of toxicity of this new class of drugs.  These PKC epsilon-specific drugs, like Bryostatin, offer the potential of treating a variety of neurologic memory disorders as described above through their “neurorescue” properties of inducing the growth of new synapses, i.e. synaptogenesis, and preventing the loss of dying neurons.

http://www.brni.org/scientific_research/clinical_trials.aspx 

 

 

 

 Here's specific info on the Bryostatin-1 clinical trial for Alzheimer's:

http://www.clinicaltrials.gov/ct2/show/NCT00606164?term=bryostatin&rank=1 



Myriam
Posted: Tuesday, September 10, 2013 12:07 PM
Joined: 12/6/2011
Posts: 3326


Thanks, Onward. I'm starting another trial soon, but will look into this one, too.
Serenoa
Posted: Tuesday, September 10, 2013 2:17 PM
Joined: 4/24/2012
Posts: 484


Ah yes, the shamans were not dumb. They knew (and know) what works. 

  

 Bryostatin is interesting and seems to have a connection to the excitotoxicity hypothesis through the NMDA receptor. But activating PKC? I though that was a bad thing.  

 

 

COMBINATION OF A NMDA RECEPTOR CHANNEL BLOCKER AND A PKC ACTIVATOR FOR TREATMENT OF ALZHEIMER'S DISEASE
 

 

Results: We demonstrated that bryostatin-1 significantly enhanced the surface expression of NMDA receptors in hippocampal neurons. Treatment with the combination of bryostatin-1 together with memantine did not increase the excitotoxicity. On the contrary, it was more effective than either bryostatine-1 or memantine alone in the prevention of neuronal death caused by Aβ, regardless of the synaptic or extrasynaptic origin of the excitotoxicity. Conclusion: This study demonstrates that the combination of bryostatin-1 with memantine has potential as a new therapeutic approach for the effective treatment of Alzheimer's disease.
 

http://patentscope.wipo.int/search/en/WO2009099563 

 

Bryostatin-1 promotes long-term potentiation via activation of PKCα and PKCε in the hippocampus

Accepted 27 August 2012

Abstract

Activation of protein kinase C (PKC) by bryostatin-1 affects various functions of the central nervous system. We explored whether bryostatin-1 influenced synaptic plasticity via a process involving PKC. Our purpose was to examine whether bryostatin-1 affected the induction of hippocampal long-term potentiation (LTP) in Schaffer-collateral fibers (CA1 fibers) of the hippocampus, and/or influenced the intracellular Ca2+ level of hippocampal neurons. We also determined the PKC isoforms involved in these processes. We found that bryostatin-1 strongly facilitated LTP induction, in a dose-dependent manner, upon single-theta burst stimulation (TBS). Further, intracellular Ca2+ levels also increased with increasing concentration of bryostatin-1. The facilitative effects of bryostatin-1 in terms of LTP induction and enhancement of intracellular Ca2+ levels were blocked by specific inhibitors of PKCα and PKCε, but not of PKCδ. Our results suggest that bryostatin-1 is involved in neuronal functioning and facilitates induction of LTP via activation of PKCα and/or PKCε.

 

http://www.sciencedirect.com/science/article/pii/S0306452212008901 

 

 


 


Lane Simonian
Posted: Tuesday, September 10, 2013 4:12 PM
Joined: 12/12/2011
Posts: 4998


I love the philosophy but am not keen on the particular natural product.  Under normal circumstances, the activation of the NMDA receptor via protein kinase C is important for memory.   

 

http://www.jbc.org/content/286/28/25187.long 

 

But the overaction of NMDA receptors is a major problem in Alzheimer's disease. 

 

http://www.jbc.org/content/286/28/25187.long 

 

Many researchers have linked protein kinase C to the non-amyloidogenic processing of the amyloid precursor protein, but I think this research finding is the correct one. 

 

Overexpression and altered metabolism of amyloid precursor

protein (APP) resulting in increased 4 kDa amyloid b peptide

(Ab) production are believed to play a major role in Alzheimer’s

disease (AD). Therefore, reducing Ab production in the brain is

a possible therapy for AD. Because AD pathology is fairly

restricted to the CNS of humans, we have established human

cerebral primary neuron cultures to investigate the metabolism

of APP. In many cell lines and rodent primary neuron cultures,

phorbol ester activation of protein kinase C (PKC) increases the

release of the secreted large N-terminal fragment of amyloid

precursor protein (sAPP) and decreases Ab release (Buxbaum 

et al., 1993; Gadzuba et al., 1993; Hung et al., 1993). In contrast,

we find that PKC activation in human primary neurons

increases the rate of sAPP release and the production of APP

C-terminal fragments and 4 kDa Ab. Our results indicate

species- and cell type-specific regulation of APP metabolism.

Therefore, our results curtail the   

the use of PKC activators in controlling

human brain Ab levels. 

 

 

 

 

 

 

http://www.jneurosci.org/content/18/8/2907.full.pdf 


Lane Simonian
Posted: Tuesday, September 10, 2013 6:32 PM
Joined: 12/12/2011
Posts: 4998


It just occurred to me: this is why mice don't get Alzheimer's disease.  The process that leads to the formation of amyloid and peroxynitrites in humans does not occur in mice.  Any attempt to increase protein kinase C activity based on mice models is likely a very bad idea. 
Myriam
Posted: Tuesday, September 10, 2013 8:05 PM
Joined: 12/6/2011
Posts: 3326


This is the study that I will be starting soon:

http://clinicaltrials.gov/show/NCT01760005


Lane Simonian
Posted: Tuesday, September 10, 2013 11:15 PM
Joined: 12/12/2011
Posts: 4998


Thanks, Myriam for the information on your clinical trial.  I think when the answers finally do come for this disease it is going to seem quite simple and people will realize that some individuals were doing something similar to it all along.
Serenoa
Posted: Wednesday, September 11, 2013 7:46 AM
Joined: 4/24/2012
Posts: 484


Good luck in the trial Myriam. Its great that you are participating. I see that Gantenerumab has been shown to induce phagocytosis of fibrillar amyloid; that is encouraging.

 

As for Bryostatin, I agree with Lane. The first study in my above post may be suspect since it is some kind of patent-related website for pharmaceuticals. Plus it is touting mementine which, from what I have read, is not very effective. And, it has been shown to activate NMDA and increase Ca+ in the neuron, and as you said Lane, which has to contribute to excitotoxicity in Alz. 


Myriam
Posted: Wednesday, September 11, 2013 3:33 PM
Joined: 12/6/2011
Posts: 3326


Serenoa wrote:

I see that Gantenerumab has been shown to induce phagocytosis of fibrillar amyloid; that is encouraging.

 


Thanks for the info,Serenoa, but what is phagocytosis of fibrillar amyloid? I googled and found this, but it's not in legalese or plain English  

 

Microglia are the principle immune effector and phagocytic cells in the CNS. These cells are associated with fibrillar beta-amyloid (fAbeta)-containing plaques found in the brains of Alzheimer's disease (AD) patients. The plaque-associated microglia undergo a phenotypic conversion into an activated phenotype and are responsible for the development of a focal inflammatory response that exacerbates and accelerates the disease process. Paradoxically, despite the presence of abundant activated microglia in the brain of AD patients, these cells fail to mount a phagocytic response to Abeta deposits but can efficiently phagocytose Abeta fibrils and plaques in vitro. We report that exposure of microglia to fAbeta in vitro induces phagocytosis through mechanisms distinct from those used by the classical phagocytic receptors, the Ig receptors (FcRgammaI and FcgammaRIII) or complement receptors. Microglia interact with fAbeta through a recently characterized Abeta cell surface receptor complex comprising the B-class scavenger receptor CD36, alpha6beta1 integrin, and CD47 (integrin-associated protein). Antagonists specific for each component of the receptor complex blocks fAbeta-stimulated phagocytosis. These data demonstrated that engagement of this ensemble of receptors is required for induction of phagocytosis. The phagocytic response stimulated by this receptor complex is driven principally by a beta(1) integrin-linked process that is morphologically and mechanistically distinct from the classical type I and type II phagocytic mechanisms. These data provide evidence for phagocytic uptake of fAbeta through a receptor-mediated, nonclassical phagocytic mechanism. 


Lane Simonian
Posted: Thursday, November 27, 2014 12:34 AM
Joined: 12/12/2011
Posts: 4998


I made a mistake on this one: bryostatin initially activates but then downregulates protein kinase C.  Protein kinase C overactivation causes the formation of peroxynitrites and can lead to the beginning of Alzheimer's disease so perhaps bryostatin may be of some use if given early and if tolerated.


Bryostatin-1 is a macrocyclic lactone derived from a marine invertebrate that binds to the regulatory domain of protein kinase C. Short-term exposure to bryostatin-1 promotes activation of PKC, whereas prolonged exposure promotes significant downregulation of PKC.


http://www.ncbi.nlm.nih.gov/pubmed/14735696


Lane Simonian
Posted: Friday, May 5, 2017 10:07 AM
Joined: 12/12/2011
Posts: 4998


I made another mistake, bryostatin-1 downregulates protein kinase C via oxidative stress. The results of the latest trial by Neurotrope for bryostatin-1 indicated some possible improvement in one test score for moderate to late Alzheimer's patients, but the improvement was not statistically significant.  And a considerable amount of data-- presumably negative--was not released by the company (the following quote was attributed to Dr. George Perry).

"Despite Neurotrope's Ph 2b being only a 3 month trial, there was a 30% drop out rate. Did you catch how Neurotrope factored those drop out patients into their PR of the trial's results? The lack of transparency from Neurotrope is disturbing and unusual. No Ph 2a scores to scrutinize, nor scores from the compassionate use patients. Only brief mention of side effects associated with the Ph 2b, no details. No scores of the 40 microgram group released. No adcs-adl scores released. Choosing to only release SIB [Severe Impairment Battery] aggregate score for the 20 microgram group. No combined overall aggregate score for all the patients enrolled in the trial."