Parallel synthesis of glycomimetic libraries: targeting a C-type lectin

Area of Science:

• Medicinal Chemistry
• Carbohydrate Chemistry
• Biochemistry

Background:

• Mannose-binding proteins, such as Mannose-Binding Protein A (MBP-A), play crucial roles in the innate immune system.
• Inhibiting the interaction between mannose-binding proteins and mannosylated surfaces is a potential therapeutic strategy for various diseases.
• Developing non-carbohydrate-based analogues offers advantages in stability and synthetic accessibility compared to natural carbohydrates.

Purpose of the Study:

• To develop novel, non-carbohydrate-based analogues of mannose.
• To synthesize libraries of these analogues using shikimic acid as a key building block.
• To evaluate the inhibitory activity of these compounds against the binding of MBP-A to a mannosylated surface.

Main Methods:

• Parallel synthesis of two distinct chemical libraries on a solid support.
• Utilized shikimic acid as a versatile starting material for analogue construction.
• Employed a high-throughput screening assay to assess the inhibition of MBP-A binding to mannosylated surfaces.

Main Results:

• Successfully synthesized two libraries comprising non-carbohydrate-based mannose analogues.
• Identified ten library members demonstrating significant inhibitory activity against MBP-A.
• The inhibitory potency of these identified compounds was comparable to that of alpha-methyl mannopyranoside.

Conclusions:

• Developed efficient methods for the parallel synthesis of novel mannose analogues.
• Shikimic acid serves as a valuable scaffold for generating carbohydrate mimetics.
• The identified compounds represent promising leads for developing inhibitors of C-type lectin-carbohydrate interactions.