Evaluation and further development of small molecule probes to study the role of prion protein in the ageing and renewal of stem cells
Lead Research Organisation:
University of Sheffield
Department Name: Chemistry
Abstract
Stem cells are particular types of cells that have unique power in regenerating themselves (self-renewal) and developing into other cell types capable of carrying out special tasks in the body. Therefore, stem cells have the potential to change the face of disease treatment by being used to repair specific tissues or to grow organs as regenerative or reparative medicine. However, stem cell research has been at the center of debate for because the majority of current research involves the use of embryonic stem cells. Embryonic stem (ES) cells used in the research are from early stage human embryos. The destruction of a human embryo is usually required in order to start a stem cell 'line'. This poses great ethical concerns and the work in this field has to be vigorously regulated. Although these cells are easy to grow in the laboratory; technical hurdles such as the availability of embryos, methods for producing particular types of tissues and organs from ES cells for intended medical use and the possibility of their rejection by the recipient because they are from different donors, further complicate the research. An alternative to ES cells is the use of adult stem cells. They can be found in the different tissues of the body, undergo self-renewal and can develop into other cell types. They have an advantage that they can be obtained from the patient's own tissue, therefore avoiding the ethical issues and problem of rejection by the immune system. Some type of adult stem cells such as haemopoietic stem (HS) cells, are already being used routinely in bone marrow transplantations. However they exist in very small numbers and this number decreases with the age of the donor. In addition, attempts to isolate and grow most adult stem cells in the laboratory have failed because they age rapidly and the ability of developing into different tissues is lost outside living environments. Therefore the main technical challenges for scientists working in this field lie in isolating them from many other cells, being able to keep them growing and reproducing without aging and maintaining their ability of development in the laboratory. The use of adult stem cells in regenerative medicine can take off rapidly once these problems are overcome. Recent studies have shown that prion proteins, which are connected with a family of deadly neurodegenerative diseases called transmissible spongiform encephalopathies (TSEs) or prion diseases (such as scrapie in goats and sheep, mad cow disease in cattle and vCJD in human) are also present in abundance on the surface of stem cells. It has been shown that in HS cells they help the renewal of these cells. This proposal aims to tackle the problem of aging and renewal in stem cell research. This will be achieved by probing the function of cellular prion protein (PrPC) on the surface of embryonal carcinoma(EC), embryonic stem (ES) cells, and adult mesenchymal stem (MS) cells, using optimised small molecule binders. EC cells will be used in initial high throughput screening to see the effects of 224 binders discovered in the applicants' group on the growth of the stem cells in general, followed by confirmation using ES cells. The active binders will then be further optimised to give rise to some high affinity binders and selected binders will be studied for their ageing and renewal in MS cells, which can potentially differentiate into bones and cartilage to be used as regenerative medicines.
Technical Summary
Stem cells can divide and renew themselves (self-renewal) whilst retaining the ability to differentiate into other cell types. Therefore, they have the potential to change the face of disease treatment by being used to repair specific tissues or to grow organs as regenerative or reparative medicine. Much research has been devoted to the study of adult stem cells as regenerative medicines as they can be obtained from the patient's own tissue, avoiding the ethical issues and problem of rejection by the immune system. However they exist in very small numbers and this number decreases with the age of the donor. Isolating them, keeping them renewing without aging in culture and retaining their differentiation ability remain a key technical challenge. Cellular prion proteins (PrPC) have been the subject of many intensive studies over more than a decade due to their connections with a family of deadly neurodegenerative diseases called transmissible spongiform encephalopathies (TSEs). Recently, it has been found that PrPC is expressed on haemopoietic stem (HS) cells and to have a role in their self-renewal. It is also suggested that PrPC may be involved in prevention of cellular ageing by preventing accumulation of defective mitochondria. This proposal aims to tackle the problem of aging and renewal in stem cell research. This will be achieved by probing the PrPC on the surface of embryonic carcinoma (EC), embryonic stem (ES) cells and mesenchymal stem(MS) cells using optimised small molecule binders. EC cells will be used in initial high throughput screening to see the effects of 224 binders discovered in the applicants' group on the growth of the stem cells in general followed by confirmation using ES cells. The initial binders will be further optimised to give rise to some high affinity binders and selected binders will be studied for their ageing and renewal in MS cells.
Publications
Abdo A
(2010)
Ligand-based virtual screening using Bayesian networks.
in Journal of chemical information and modeling
Chen B
(2010)
Combination Rules for Group Fusion in Similarity-Based Virtual Screening.
in Molecular informatics
Chen B
(2009)
Evaluation of a Bayesian inference network for ligand-based virtual screening
in Journal of Cheminformatics
Guo K
(2008)
Synthesis and evaluation of a focused library of pyridine dicarbonitriles against prion disease.
in European journal of medicinal chemistry
Guo K
(2009)
Exploring catalyst and solvent effects in the multicomponent synthesis of pyridine-3,5-dicarbonitriles.
in The Journal of organic chemistry
Heal W
(2007)
Library synthesis and screening: 2,4-diphenylthiazoles and 2,4-diphenyloxazoles as potential novel prion disease therapeutics.
in Journal of medicinal chemistry
Mohanty ST
(2012)
A small molecule modulator of prion protein increases human mesenchymal stem cell lifespan, ex vivo expansion, and engraftment to bone marrow in NOD/SCID mice.
in Stem cells (Dayton, Ohio)
Thompson M
(2010)
Structure-Activity Relationship Refinement and Further Assessment of Indole-3-glyoxylamides as a Lead Series against Prion Disease
in ChemMedChem
Thompson MJ
(2012)
Synthesis and evaluation of 1-amino-6-halo-ß-carbolines as antimalarial and antiprion agents.
in ChemMedChem
Thompson MJ
(2009)
Design, synthesis, and structure-activity relationship of indole-3-glyoxylamide libraries possessing highly potent activity in a cell line model of prion disease.
in Journal of medicinal chemistry
Thompson MJ
(2011)
Discovery of 6-substituted indole-3-glyoxylamides as lead antiprion agents with enhanced cell line activity, improved microsomal stability and low toxicity.
in European journal of medicinal chemistry
Thompson MJ
(2010)
Improved 2,4-diarylthiazole-based antiprion agents: switching the sense of the amide group at C5 leads to an increase in potency.
in ChemMedChem
Thompson MJ
(2009)
Development of a diversity-oriented approach to oxazole-5-amide libraries.
in The Journal of organic chemistry
Thompson MJ
(2011)
2,4-diarylthiazole antiprion compounds as a novel structural class of antimalarial leads.
in Bioorganic & medicinal chemistry letters
Thompson MJ
(2009)
Ugi reactions with ammonia offer rapid access to a wide range of 5-aminothiazole and oxazole derivatives.
in The Journal of organic chemistry
Description | Cellular protein, PrPC, is required to keep bone marrow MSC in proliferating state and small molecule indole compound, 689, can enhance the proliferation of MSC, more profound when they are in aged state via regulating the SOD2 activities. The MSC cultured in the presence of 689 can increase the bone mass and quality in Osteophorisis mice model. |
Exploitation Route | The findings were published and cited by others working in the field. They were also taken forward by the applicants as bases in the further grant applications. |
Sectors | Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology |
Description | The findings have been used by applicants and others for further research and funding applications. |
First Year Of Impact | 2010 |
Sector | Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology |
Impact Types | Societal |
Description | EPSRC Theme Day |
Geographic Reach | National |
Policy Influence Type | Contribution to a national consultation/review |
Impact | The recommendation of the theme day reshaped the RU policy and priority on healthcare, especially in regenerative medicine field. |
Description | Assessment of the Fanconi Anaemia pathway and its inhibition in Glioblatoma Multiforme |
Amount | £66,000 (GBP) |
Organisation | Weston Park Hospital |
Department | Weston Park Hospital Cancer Charity |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2013 |
End | 12/2013 |
Description | Assessment of the Fanconi Anaemia pathway and its inhibition in Glioblatoma Multiforme |
Amount | £153,000 (GBP) |
Organisation | Yorkshire Cancer Research |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2014 |
End | 12/2016 |
Description | De Novo Design Tool |
Amount | £120,576 (GBP) |
Organisation | Cambridge Crystallographic Data Centre |
Sector | Academic/University |
Country | United Kingdom |
Start | 10/2009 |
End | 09/2011 |
Description | Design and Synthesis of Pharmaceutically Relevant Chemical Entities |
Amount | £191,696 (GBP) |
Organisation | Innovate UK |
Sector | Public |
Country | United Kingdom |
Start | 09/2010 |
End | 08/2013 |
Description | Design and Synthesis of Pharmaceutically Relevant Chemical Entities |
Amount | £192,000 (GBP) |
Funding ID | 007548 |
Organisation | Innovate UK |
Sector | Public |
Country | United Kingdom |
Start | 09/2010 |
End | 09/2013 |
Description | Development of novel antibiotics against anthrax based upon currently recommended drugs ciprofloxacin and other existing drugs using chimeric approaches |
Amount | £568,000 (GBP) |
Funding ID | HO/0407270 |
Organisation | Government of the UK |
Sector | Public |
Country | United Kingdom |
Start | 06/2008 |
End | 05/2011 |
Description | Diagnostic and Drug Discovery Initiative for Alzheimer's Disease (D3i4AD) |
Amount | € 2,209,000 (EUR) |
Funding ID | 612347 |
Organisation | European Commission |
Department | Seventh Framework Programme (FP7) |
Sector | Public |
Country | European Union (EU) |
Start | 10/2014 |
End | 09/2018 |
Description | Optimisation And Further Biological Evaluation Of Novel Broad Spectrum Antibiotics |
Amount | £101,000 (GBP) |
Organisation | Government of Catalonia |
Department | Department of Health |
Sector | Public |
Country | Spain |
Start | 10/2011 |
End | 03/2013 |
Description | Stem Cell, Prion Protein, and Azlheimer's Disease: A Prion Chemical Biology Network (PCBNet) |
Amount | £224,055 (GBP) |
Funding ID | EP/I037296/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 05/2011 |
End | 08/2013 |
Title | SMB cell line |
Description | It was made available to research groups interested. |
Type Of Material | Biological samples |
Year Produced | 2011 |
Provided To Others? | Yes |
Impact | It provides a tool to assess the antiprion activity of compounds. |
Title | Small molecule chemical probes |
Description | Small molecules that can enhance the proliferation of stem cells |
Type Of Material | Technology assay or reagent |
Year Produced | 2011 |
Provided To Others? | Yes |
Impact | The compounds are available to research community interested |
Title | Chemical compound library |
Description | It contains chemical compounds synthesised in my group. |
Type Of Material | Database/Collection of data |
Year Produced | 2010 |
Provided To Others? | Yes |
Impact | It has potential to be developed as novel therapeutics. |
Description | Assessment of DMPK properties of small molecule antiprion compounds in mice models |
Organisation | University of California, San Francisco |
Country | United States |
Sector | Academic/University |
PI Contribution | Preparation of small molecule antiprion compounds |
Collaborator Contribution | Assessment of DMPK properties of small molecule antiprion compounds in mice models |
Impact | Results to be published |
Start Year | 2013 |
Description | Investigate the role of prion protein in Alzheimner's disease |
Organisation | Eli Lilly & Company Ltd |
Country | United Kingdom |
Sector | Private |
PI Contribution | know-how and 12 years experience in prion research field |
Collaborator Contribution | Strong track record in drug discovery in commercial sector |
Impact | successful studentship and EU grants |
Start Year | 2013 |
Description | Test and validation of the role of prion protein in Alzheimer's disease models |
Organisation | Amorfix Life Sciences Ltd |
Country | Canada |
Sector | Private |
PI Contribution | Design the epitope of antibody for Abeta amyloid protein |
Collaborator Contribution | Production of anti Abeta amyloid antibody |
Impact | A successful application of EU project |
Start Year | 2011 |
Description | small molecules that influence Prnp expression and differentiation potential of canine BM-MSCs |
Organisation | Utrecht University |
Department | Faculty of Veterinary Medicine |
Country | Netherlands |
Sector | Hospitals |
PI Contribution | Proof of concept validation of small molecules that influence Prnp expression and differentiation potential of canine BM-MSCs. |
Collaborator Contribution | Test the small molecules in canine BM-MSCs. |
Impact | Results to be published. |
Start Year | 2014 |
Title | INDOLE DERIVATIVES FOR THE STIMULATION OF STEM CELL PROLIFERATION |
Description | The present invention relates to indole derivatives of formula (I) and Formula (II) which possess potent antiprion activity and stem cell proliferative properties. The invention also relates to the use of such compounds to treat prion-related diseases and in stem cell therapies. |
IP Reference | WO2010139982 |
Protection | Patent granted |
Year Protection Granted | 2010 |
Licensed | No |
Impact | Novel indole compounds as regenerative medicine. |
Title | THIAZOLE AND OXAZOLE DERIVATIVES FOR USE IN THE TREATMENT OF PRION DISEASES, CANCER AND CONDITIONS OF THE CENTRAL NERVOUS SYSTEM AS WELL AS IN THE REGULATION OF STEM CELLS |
Description | Compounds of the formula (I) are provided: Fomula (I) wherein X, Y, R1, R2 and R3 are as defined in the specification. The compounds may be useful in the treatment of various diseases and conditions, in particular prion diseases. |
IP Reference | WO2008090382 |
Protection | Patent granted |
Year Protection Granted | 2008 |
Licensed | No |
Impact | Novel antiprion therapeutics. |
Description | 8th International Symposium for Chinese Medicinal Chemists |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | International conference. |
Year(s) Of Engagement Activity | 2012 |
Description | 9th IUPAC International Symposium on Biomolecular Chemistry |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | International conference. |
Year(s) Of Engagement Activity | 2012 |
Description | Prion 2012 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Raise public awareness and share scientific information. |
Year(s) Of Engagement Activity | 2012 |
Description | Royal Society of Chemistry Biological and Medicinal Chemistry Sector (BMCS) 2nd RSC Symposium on Chemical Biology for Drug Discovery 20th -21st of March 2012 AstraZeneca, Alderley Park, Macclesfield, UK |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Raise public awareness in stem cell, the role of prion protein and regenerative medicine. |
Year(s) Of Engagement Activity | 2012 |
Description | prion 2013 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Raise public awareness and share scientific information |
Year(s) Of Engagement Activity | 2013 |
Description | prion chemical biology article |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Raise public awareness |
Year(s) Of Engagement Activity | 2015 |