PRECLINICAL DRUG DISCOVERY AND DEVELOPMENT FOR A NOVEL ALZHEIMER’S DISEASE DRUG : - A stroy of an orphan -
(2019) KEMT30 20191Department of Chemistry
- Abstract
- Alzheimer’s disease is a severe neurodegenerative disease, affecting the life of millions of patients and those who stand close to them. There is an urgent need for new effective medical treatments targeting this disease, as up to now, there is none. GPR3, a highly constitutively active orphan G protein coupled receptor, was found to interact with several different molecules that are known to play important roles in the amyloidogenic processing of Amyloid Precursor Protein (APP). This processing of APP results in the generation of Amyloid β (Aβ), hallmark and possibly causative agent of Alzheimer’s disease, according to the leading Amyloid hypothesis. According to our hypothesis which builds on strong peer-reviewed in-vivo science and... (More)
- Alzheimer’s disease is a severe neurodegenerative disease, affecting the life of millions of patients and those who stand close to them. There is an urgent need for new effective medical treatments targeting this disease, as up to now, there is none. GPR3, a highly constitutively active orphan G protein coupled receptor, was found to interact with several different molecules that are known to play important roles in the amyloidogenic processing of Amyloid Precursor Protein (APP). This processing of APP results in the generation of Amyloid β (Aβ), hallmark and possibly causative agent of Alzheimer’s disease, according to the leading Amyloid hypothesis. According to our hypothesis which builds on strong peer-reviewed in-vivo science and recent published findings on this topic, finding an inverse agonist which successfully inhibits the β-Arrestin 2 (β-Arr2) signaling pathway of GPR3 should result in a significant decrease of Aβ peptides and -plaques as well as improvements in cognitive decline. Our research platform consists of a bipartite screening platform, enabling us to effectively pursue finding a β-Arr2 biased inverse agonist for GPR3. Cannabidiol (CBD), the first natural compound confirmed to be an inverse agonist for GPR3, is able to decrease β-Arr2 coupling to GPR3 by ~25%. Our primary screening assay has been validated with CBD, and is in line with the findings in the literature. It has been shown, that a 50 % reduction - by genetic manipulation – of the GPR3 receptor in AD model mice lessens the amyloid burden by more than 50%. Therefore our main aim is to find a more efficacious and potent biased inverse agonist which is able to inhibit the β-Arr2 signaling pathway, while not affecting the G-protein coupled signaling pathway. By employing such an inverse agoinst we expect a decrease in generation of Aβ, while the favourable effects of G protein coupled signaling, such as promotion of neurite outgrowth would remain. (Less)
- Popular Abstract
- The lack of effective treatment for Alzheimer’s disease (AD) is one of the biggest unmet medical needs of the 21st century. 10 % of people over the age of 65 are affected and 50 % over the age 85. By 2050, more than 130 million people are projected to be affected globally. None of the current approved AD drugs on the market have any effect on the progression of the disease, they only offer marginal symptomatic relief. Furthermore, no drug has entered the market in almost 20 years. Thus, there is an enormous need for new and different approaches to resolve this issue.
Currently, the pharmaceutical industry is largely focused on two different strategies. One strategy is known as immunotherapy – ways to stimulate the body’s own immune system... (More) - The lack of effective treatment for Alzheimer’s disease (AD) is one of the biggest unmet medical needs of the 21st century. 10 % of people over the age of 65 are affected and 50 % over the age 85. By 2050, more than 130 million people are projected to be affected globally. None of the current approved AD drugs on the market have any effect on the progression of the disease, they only offer marginal symptomatic relief. Furthermore, no drug has entered the market in almost 20 years. Thus, there is an enormous need for new and different approaches to resolve this issue.
Currently, the pharmaceutical industry is largely focused on two different strategies. One strategy is known as immunotherapy – ways to stimulate the body’s own immune system to target and remove the protein clumps found in the brain of patients with AD. These protein clumps are mainly composed of a peptide called Amyloid β (Aβ). The other strategy being widely used is the creation of compounds that stop the activity of the enzymes directly involved in the production of Aβ. Enzymes, being macromolecules that speed up chemical reactions in biological systems, in this context specifically, the cleavage of a protein called amyloid precursor protein (APP) into Aβ. Both of these strategies have generated many promising drug candidates over the last decade, but so far, all have failed in the clinical development phases, due to lack of therapeutic effects and/or severe side effects.
We chose a different approach to tackle this disease, namely by targeting a receptor recently known to affect the progression of AD in mice. This specific receptor is found to be involved in the Aβ generation, and is mostly found across the regions of brain where the protein clumps start developing in AD patients.
There are many different types of cell receptors throughout nature. Simply described, all cell receptors are proteins with one main function, detecting a highly specific signal and then transducing that signal into an equally specific secondary signaling pathway. At the end of such a signaling pathway, a specific cell response is generated. In animals G protein coupled receptors constitute the largest subclass of receptors and are named after their specific type of signaling
mechanisms. There are more than 800 G protein coupled receptors expressed throughout the human body, and most of them are involved in the central nervous system, in functions such as tasting or smelling. Our attention has been focused on G protein coupled receptor 3 (GPR3) which recently has been found to affect the processing of APP which results in the generation of Aβ plaques. In 2015 it was discovered that if we reduce the amount of this specific receptor by half in mouse models for AD, a significant decrease of the protein clumps, as well as less cognitive impairment, can be achieved. Reducing the amount of GPR3, or inhibiting its function, should theoretically lead to the same outcome, less brain Aβ clumps in the brain and less deterioration of cognition. GPR3 has two main signaling pathways that affect the cells, one is an advantegous attribute towards cell functioning, e.g. promotes the connections between neurons; the other way results in the increased generation of Aβ peptides. Our main aim has been to find a compound capable of inhibiting the ability of GPR3 to promote the production of Aβ, while not affecting its advantageous abilities. Such a compound would constitute a novel drug candidate for AD and possess many advantages. It would target a highly druggable receptor not previously utilized and also exploit a new Mechanism of Action to reduce the amyloid clumps in the brain. Finding a way to successfully manipulate this receptor could result in a novel AD drug and have a favourable outcome for millions of people. (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/8991949
- author
- Tóth, Albert LU
- supervisor
- organization
- course
- KEMT30 20191
- year
- 2019
- type
- H2 - Master's Degree (Two Years)
- subject
- keywords
- Protein science, Alzheimer's disease, G protein coupled receptors, biochemistry
- language
- English
- id
- 8991949
- date added to LUP
- 2023-06-28 13:54:48
- date last changed
- 2023-06-28 13:54:48
@misc{8991949,
abstract = {{Alzheimer’s disease is a severe neurodegenerative disease, affecting the life of millions of patients and those who stand close to them. There is an urgent need for new effective medical treatments targeting this disease, as up to now, there is none. GPR3, a highly constitutively active orphan G protein coupled receptor, was found to interact with several different molecules that are known to play important roles in the amyloidogenic processing of Amyloid Precursor Protein (APP). This processing of APP results in the generation of Amyloid β (Aβ), hallmark and possibly causative agent of Alzheimer’s disease, according to the leading Amyloid hypothesis. According to our hypothesis which builds on strong peer-reviewed in-vivo science and recent published findings on this topic, finding an inverse agonist which successfully inhibits the β-Arrestin 2 (β-Arr2) signaling pathway of GPR3 should result in a significant decrease of Aβ peptides and -plaques as well as improvements in cognitive decline. Our research platform consists of a bipartite screening platform, enabling us to effectively pursue finding a β-Arr2 biased inverse agonist for GPR3. Cannabidiol (CBD), the first natural compound confirmed to be an inverse agonist for GPR3, is able to decrease β-Arr2 coupling to GPR3 by ~25%. Our primary screening assay has been validated with CBD, and is in line with the findings in the literature. It has been shown, that a 50 % reduction - by genetic manipulation – of the GPR3 receptor in AD model mice lessens the amyloid burden by more than 50%. Therefore our main aim is to find a more efficacious and potent biased inverse agonist which is able to inhibit the β-Arr2 signaling pathway, while not affecting the G-protein coupled signaling pathway. By employing such an inverse agoinst we expect a decrease in generation of Aβ, while the favourable effects of G protein coupled signaling, such as promotion of neurite outgrowth would remain.}},
author = {{Tóth, Albert}},
language = {{eng}},
note = {{Student Paper}},
title = {{PRECLINICAL DRUG DISCOVERY AND DEVELOPMENT FOR A NOVEL ALZHEIMER’S DISEASE DRUG : - A stroy of an orphan -}},
year = {{2019}},
}