Structure based design of inhibitors targeting galectin-8
Author(s)
Primary Supervisor
Blanchard, Helen
Other Supervisors
Kishor, Chandan
Houston, Todd A
Year published
2020-08-12
Metadata
Show full item recordAbstract
Galectins are [beta]-galactoside binding proteins that are found in all type of living organisms, and involved in many physiological functions such as inflammation, immune responses, cell adhesion, growth and migration, apoptosis, etc. Due to their association with the progression of several metabolic and disease conditions, galectins are recognised as important targets for the drug development. Galectin-8 is involved in several biological functions such as cell adhesion and growth, immune responses, inflammation, new blood vessel formation, osteoblast and osteoclast differentiation, cancer growth and metastasis, platelet ...
View more >Galectins are [beta]-galactoside binding proteins that are found in all type of living organisms, and involved in many physiological functions such as inflammation, immune responses, cell adhesion, growth and migration, apoptosis, etc. Due to their association with the progression of several metabolic and disease conditions, galectins are recognised as important targets for the drug development. Galectin-8 is involved in several biological functions such as cell adhesion and growth, immune responses, inflammation, new blood vessel formation, osteoblast and osteoclast differentiation, cancer growth and metastasis, platelet aggregation. Structurally, galectin-8 is a tandem-repeat type galectin, comprising an N-terminal and (galectin-8N) C-terminal (galectin-8C) CRD domain connected by a peptide linker. Superimposition of both the CRDs reveals structural differences between their carbohydrate binding sites. The individual N- and C-CRD domain shows similar functional roles which are observed with full length galectin-8, however, their potency is less compared to full length galectin-8. Several structural investigations showed that the N-terminal domain preferentially binds to the anionic sialylated, sulphated oligosaccharides due to the presence of the unique Arg59, which is only present in galectin-8N and hence is unique amongst all galectins. The main body of research presented in this thesis is about design, synthesis of selective and potent galectin-8N antagonists by utilising a structure-based drug design approach. [...]
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View more >Galectins are [beta]-galactoside binding proteins that are found in all type of living organisms, and involved in many physiological functions such as inflammation, immune responses, cell adhesion, growth and migration, apoptosis, etc. Due to their association with the progression of several metabolic and disease conditions, galectins are recognised as important targets for the drug development. Galectin-8 is involved in several biological functions such as cell adhesion and growth, immune responses, inflammation, new blood vessel formation, osteoblast and osteoclast differentiation, cancer growth and metastasis, platelet aggregation. Structurally, galectin-8 is a tandem-repeat type galectin, comprising an N-terminal and (galectin-8N) C-terminal (galectin-8C) CRD domain connected by a peptide linker. Superimposition of both the CRDs reveals structural differences between their carbohydrate binding sites. The individual N- and C-CRD domain shows similar functional roles which are observed with full length galectin-8, however, their potency is less compared to full length galectin-8. Several structural investigations showed that the N-terminal domain preferentially binds to the anionic sialylated, sulphated oligosaccharides due to the presence of the unique Arg59, which is only present in galectin-8N and hence is unique amongst all galectins. The main body of research presented in this thesis is about design, synthesis of selective and potent galectin-8N antagonists by utilising a structure-based drug design approach. [...]
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Thesis Type
Thesis (PhD Doctorate)
Degree Program
Doctor of Philosophy (PhD)
School
Institute for Glycomics
Copyright Statement
The author owns the copyright in this thesis, unless stated otherwise.
Subject
galectins
galectin-8N antagonists
structure-based drug design