Searching for Glycomimetics That Target Protein Misfolding in Rare Diseases: Successes, Failures, and Unexpected Progress Made in Organic Synthesis

This account describes our efforts aimed toward the discovery of original glycomimetics that target protein misfolding to fight rare diseases, with a focus on cystic fibrosis and Gaucher disease. The pursuit of this goal has led to promising leads and strategies, with the first description of a multivalent effect for correcting protein-folding defects in cells, and has also driven unexpected progress in synthetic methodology. 1Introduction 2The Therapeutic Targets: Challenges and Stakes 2.1Glycosphingolipid Lysosomal Storage Disorders 2.2Cystic Fibrosis 3Synthetic Targets Met, Potent Leads Gained 3.1Synthetic Targets Met 3.2A First Detour via a Substrate Reduction Therapy Approach 3.3Potent Leads Gained 4Synthetic Targets Missed, Synthetic Progress Gained 4.1A New Domino Reaction 4.2Extending the Scope of C-H Amination 4.3A New Versatile Amino Protecting Group 5Multivalency: A New and Promising Approach 5.1How It Began 5.2Gaucher Disease 5.3Cystic Fibrosis 6Conclusion