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Combinatorial synthesis of a hyaluronan based polysaccharide library for enhanced CD44 binding
Kunli Liu1, William M McCue2, Chia-Wei Yang1
1Department of Chemistry, Michigan State University, 578 S. Shaw Lane, East Lansing, MI 48824, USA.
Carbohydrate Polymers
|November 13, 2022
Summary
Researchers modified hyaluronan (HA) using the Ugi reaction to create new compounds. These modified HA molecules show enhanced binding to the CD44 receptor, offering potential for new therapeutic strategies.
Area of Science:
- Biochemistry
- Chemical Biology
- Glycobiology
Background:
- Hyaluronan (HA) is a crucial glycosaminoglycan involved in numerous biological processes.
- Cluster of Differentiation 44 (CD44) is the primary receptor for HA in humans, mediating various cellular functions.
Purpose of the Study:
- To develop novel hyaluronan derivatives with enhanced binding affinity for the CD44 receptor.
- To explore the utility of the four-component Ugi reaction for modifying HA.
Main Methods:
- Synthesis of 36 HA-like polysaccharides via Ugi reaction by modifying HA's carboxyl group with amine, aldehyde, and isocyanide.
- Evaluation of CD44 binding using surface plasmon resonance (SPR) and cellular assays.
- In vivo validation using a mouse tumor model.
- Application of machine learning (Ski-learn) for data analysis and prediction.
Main Results:
- Identification of two lead compounds exhibiting superior CD44 binding compared to unmodified HA.
- Confirmation of enhanced binding through SPR, cellular studies, and in vivo mouse tumor models.
- Machine learning analysis achieved over 80% prediction accuracy for compound efficacy.
Conclusions:
- Modification of hyaluronan using the Ugi reaction is a viable strategy for creating potent CD44 binders.
- This approach holds promise for developing new therapeutics targeting HA-CD44 interactions.
