Discovery, fundamental recognition, and applications of non-carbohydrate and of macrocyclic glycomimetics targeting CNS

A first aim is to improve understanding of protein-ligand binding. Emphasis is on poorly understood entropic changes and how this is affected by ligand (macro)cyclization.

A multidisciplinary approach is planned with design and synthesise systematically altered compounds to study interactions with galactoside-binding model proteins, galectins, in protein binding assays and ITC during Y1-4 and in selected cases during Y3-4 with Xray, nmr, and computational methods.

Two ligand design strategies are planned: 1) Stepwise deprivation of the ligand galactoside pyranose ring C and O atoms to give smaller threitol, glycerol, and ethanol ligand fragments and 2) incorporation of a ligand galactopyranose in larger macrocycles of varying flexibility.

This will provide insight into ligand cyclization effects on galectin binding thermodynamics and allow for design of non-galactopyranose-derived inhibitors with improved PK-ADME properties, which paves the way for the second aim to discover galectin inhibitors reaching CNS.

CNS availability will be studied in an MDCK assay Y1-4, while PET-studies of organ distribution (i.e. the brain) will be performed during Y3-4. CNS-available galectin inhibitors will be evaluated during Y3-4 in Alzheimers and in brain tumor models.

Reaching this aim will lead to the first described CNS-active lectin inhibitors and conceptually novel compounds treating the devastating and galectin-dependent Alzheimer’s disease and brain tumors, such as glioblastoma.