Autofagosytoosin aktivoiminen aineella "X"

Leevi

ALStuttu:n jäsen
Washington State University:ssä menossa mielenkiintoista tutkimusta.

Autofagosytoosi (https://fi.wikipedia.org/wiki/Autofagosytoosi) -prosessi ei neurologisissa sairauksissa toimi kunnolla ja tutkijat pyrkivät korvaamaan lanthionine ketimine (https://en.wikipedia.org/wiki/Lanthionine_Ketimine) -nimisen aminohappojen aineenvaihduntatuotteen aineella jonka nimeä ei ole kerrottu julkisuuteen. Haasteena näyttäisi saada aine kuljetettua aivoihin. Lanthionine ketiminelle en äkkiseltään onnistunut löytämään suomennosta.


https://news.wsu.edu/2016/03/16/wsu-searches-drugs-fight-als-alzheimers-brain-disorders/

WSU searches for brain drugs to fight ALS, Alzheimer’s, more

Published On March 16, 2016

By Lori Maricle, College of Pharmacy

SPOKANE, Wash. – Repairing the brain’s “house-cleaning function,” which could help people with Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis (ALS) and 100 other diseases, is the focus of recently funded research at Washington State University.

The work will make a point of including undergraduate researchers.

“Who wouldn’t want to help fight diseases like these?” said Travis Denton, a medicinal chemist at the WSU College of Pharmacy in Spokane. He was awarded $446,233 over three years from the National Institutes of Neurological Disorders and Stroke to investigate new drugs to treat neurological disorders related to autophagic dysfunction.

Autophagy is a process that recycles and clears out old or damaged particles and proteins from cells.

“Autophagy helps defend against metabolic stress, maintains homeostasis and safeguards genomic stability. It’s the house-cleaning function of the brain,” said Denton.

For patients with neurologic disorders, autophagy doesn’t work properly, or at all.

“This would be as if the housekeeper – who typically comes over once every week – just stops coming over all together,” said Denton. “In the body, when this happens, cells begin do die and the system degenerates.

“My collaborator in this project, Dr. Kenneth Hensley at the University of Toledo, has uncovered a fundamentally new way to activate autophagy,” said Denton. “The new chemicals being prepared in our lab are developed to selectively activate autophagy – recruiting the housekeepers back to the brain and, hopefully, regenerating the system.”

The Hensley compound mimics the natural brain metabolite lanthionine ketimine (LK) that activates autophagy by:

• Keeping abnormal proteins from building up and potentially shutting down major organs (heart, liver and nervous system, to name a few)
• Protecting the brain’s functions of learning and memory against neurotransmitter toxicity
• Activating or increasing the activity of proteins that promote the initial growth, maintenance and survival of brain neurons
• Enhancing the movement of proteins, lipids and other cell parts through the cytoplasm of cell bodies.

ALS, Alzheimer’s disease, Parkinson’s disease, traumatic brain injury and aging differ fundamentally but all share the element of autophagic dysfunction.

“This new funding means we can start the medicinal chemistry investigation into the nature of the compound’s membrane (brain) permeability, esterase liability and overall effectiveness as a drug,” said Denton.

In addition, “one of the goals of this proposal is to give undergraduate students the opportunity to experience all that graduate school in the biomedical sciences at an R1 university setting has to offer,” he said.

While the WSU College of Pharmacy is primarily a professional (Pharm.D.) and graduate education (Ph.D.) college, Denton’s lab has agreements with Gonzaga University, Whitworth University and Eastern Washington University so undergraduate students can obtain course credits.

Getting students into the lab where they can see the real-world application of the basic chemistry that is still fresh in their memory does a lot to spark their interest, said Denton.

“Being able to create a drug that could help, or cure, a devastating disease like ALS is what turned me from pre-med as an undergraduate to studying medicinal chemistry,” he said.

The research complements WSU’s Grand Challenges initiative stimulating research to address some of society’s most complex issues. The work is particularly relevant to the challenge “Sustaining Health: The Uncompromising Pursuit of Healthier People and Communities,” including its theme of changing the course of disease. The grant number is R15NS093594.
 

Leevi

ALStuttu:n jäsen
Tuolta videolta käy selville että aine "X" on englanniksi "Lanthionine ketimine ethyl ester".
Se pitäisi saada veriaivoesteen yli, LKEE-molekyyli on tarkoitus "naamioida" johonkin kuljetusmolekyyliin tms, siten että perillä aivoissa aivojen omat entsyymit poistavat "naamioinnin" ja LKEE-molekyyli on perillä.
Hiirillä veriaivoesteen ylitys on videon mukaan saatu aikaan, mutta ei vielä ihmisillä.
 

Leevi

ALStuttu:n jäsen
Aiheeseen liittyvä patentti luettavissa:
https://www.google.ch/patents/US7683055
https://www.google.ch/patents/US7683055

Lainaus:

"One aspect of the present invention is the improved delivery of LK and/or LK derivatives to target cells. The improved delivery comprises improved delivery through cell membranes and/or improved permeability through the blood brain barrier (BBB). The invention accomplishes the improved delivery through derivatization of the LK to form LK esters (LKEs) and LK amides (LKAs). The invention contemplates that the R1 and R2 groups of the structure:"

(kuva linkin takana)

can be substituted with one or more functional groups that will facilitate the transport of the resulting molecule through the BBB. In some of these embodiments, the functional group interacts with BBB-specific transport mechanisms. For example, an ascorbyl derivative of LK are be expected to take advantage of BBB ascorbyl transporters. Also, certain amino acid esters or amide derivatives of LK are expected to be readily transported across the BBB by means of BBB transport enzymes. In certain embodiments, R1 and/or R2 is a serinyl group. Methods of making ascorbyl, dehydroascorbyl, and amino acid esters of drugs containing carboxylic acids are well-known in the art. "

Toinen patentti, jonka mukaan Glutationi-Lanthionine (gLan) saattaa olla jopa tehokkaampi aine kuin LKE:

http://www.google.com/patents/US20130209366

"The gLan compositions diminish inflammatory cell activation, promote neurite outgrowth, slow neurodegeneration in a variety of diseases. Such diseases include amyotrophic lateral sclerosis (ALS) and Alzheimer's disease, among others. Additional methods related to use of gLan against behavioral disorders such as schizophrenia are also within the scope of the present invention. The gLan compositions herein are useful for the same purposes as the LK derivatives discussed in U.S. Pat. No. 7,683,055 but have the advantages of being more chemically stable, are more capable of crossing the blood-brain barrier, and demonstrate greater efficacy in a mouse model of ALS than LK-ethyl ester (LKE)."
 
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