Development of a small molecule inhibitor of Chst11 for restoration of cognition in Alzheimer's disease
Lead Research Organisation:
University of Leeds
Department Name: Sch of Chemistry
Abstract
The project aims to restore cognition in AD through regenerative biology based on the central nervous system extracellular matrix. We have shown that chondroitin 4-sulphate (C4S), the product of chondroitin sulphate 4-sulfotransferase (Chst11), limits plasticity in the perineuronal nets (PNNs). In late ageing, sulphation changes in the PNNs turn off compensatory plasticity, triggering cognitive decline. Removal of chondroitin sulphates in the PNNs restores memory deficit in a mouse model of Alzheimer's disease. The ratio between chondroitin 4-sulphates and chondroitin 6-sulphates (C6S) increases in the aged brain and transgenic mice with high C4S:C6S ratio demonstrated early memory loss as young as 3-months old.
The objective of the project will be to design and optimise small-molecule inhibitors of chondroitin sulphate 4-sulfotransferase (Chst11) to restore cognitive decline. We have recently identified two classes of small molecule inhibitors of Chst11 with low uM potency which have the potential for further optimisation. No competitor small molecule inhibitors of Chst11 have been described.
This studentship aims to achieve the following objectives:
1. To demonstrate the ability to design drug-like and potent inhibitors of Chst11
2. To demonstrate the potential for incorporation of structural hypothesis to binding based on in silico design and aim to support this work through mutation studies and collaboration with Oxford and others in the Astbury Centre at Leeds for co-ligand structure determination
3. To optimise the inhibitors for drug-likeness and pharmaceutical and pharmacokinetic properties consistent with a bioavailable agent
4. To validate the use of inhibitors in supporting the understanding of the link between AD, PNN and Chst11 biology
A key focus of this project will be to optimise the inhibitors for Chst11 potency, selectivity and physiochemical properties consistent with the properties of an orally bioavailable therapeutic. This will be achieved by strategic modification of the compounds by consideration of SAR and rationalisation of a structure-based component through use of protein structural models and a pharmacophore model for Chst11 modulation, as well as optimisation of physicochemical properties directed by computational prediction and in vitro assay. All synthesised compounds will be tested for Chst11 inhibition using appropriate biochemical and cellular in vitro assays and for selectivity using a panel of close Chst homologues. The overall aim of the project will be to generate a compound or compounds with appropriate potency, selectivity and pharmacokinetic properties to be progressed to suitable in vitro and in vivo determination of Chst11 function linked to AD.
The objective of the project will be to design and optimise small-molecule inhibitors of chondroitin sulphate 4-sulfotransferase (Chst11) to restore cognitive decline. We have recently identified two classes of small molecule inhibitors of Chst11 with low uM potency which have the potential for further optimisation. No competitor small molecule inhibitors of Chst11 have been described.
This studentship aims to achieve the following objectives:
1. To demonstrate the ability to design drug-like and potent inhibitors of Chst11
2. To demonstrate the potential for incorporation of structural hypothesis to binding based on in silico design and aim to support this work through mutation studies and collaboration with Oxford and others in the Astbury Centre at Leeds for co-ligand structure determination
3. To optimise the inhibitors for drug-likeness and pharmaceutical and pharmacokinetic properties consistent with a bioavailable agent
4. To validate the use of inhibitors in supporting the understanding of the link between AD, PNN and Chst11 biology
A key focus of this project will be to optimise the inhibitors for Chst11 potency, selectivity and physiochemical properties consistent with the properties of an orally bioavailable therapeutic. This will be achieved by strategic modification of the compounds by consideration of SAR and rationalisation of a structure-based component through use of protein structural models and a pharmacophore model for Chst11 modulation, as well as optimisation of physicochemical properties directed by computational prediction and in vitro assay. All synthesised compounds will be tested for Chst11 inhibition using appropriate biochemical and cellular in vitro assays and for selectivity using a panel of close Chst homologues. The overall aim of the project will be to generate a compound or compounds with appropriate potency, selectivity and pharmacokinetic properties to be progressed to suitable in vitro and in vivo determination of Chst11 function linked to AD.
Organisations
People |
ORCID iD |
| Richard Foster (Primary Supervisor) | |
| James Duncan (Student) |