Rational design and study of peptide ligands for carbohydrates : applications in understanding bimolecular recognition and in targeting of biomolecules

Abstract

The ability of biomolecules to recognize one another forms the basis of life as we know it. Beginning from fundamental knowledge on molecular interactions, complex systems can be broken down to understand biological processes, and this knowledge may be exploited for the benefit of humankind – whether in diagnostics, therapeutics, or any number of biotechnological applications. Carbohydrates, which display exquisite recognition skills in biology, offer great potential for study and for use as ligands in this regard. The development of carbohydrate-binding ligands may serve to open up new application spaces in comparison to the more developed protein sphere, while simultaneously providing insights into molecular mechanisms of carbohydrate recognition. The application of rational design principles to such efforts provides the benefit of breaking down the complexities of molecular interaction into rules that can lead to enhanced fundamental understanding of systems in hand.

Peptides as ligands in the targeting of carbohydrates may serve two purposes – to develop novel ligands that exhibit characteristics (like low molecular weight and production ease) amenable for application as well to promote understanding of carbohydrate biological recognition. Specifically, in regard to the latter purpose, peptides offer the possibility to study and exploit natural carbohydrate interactions as the basis for rational design. In this work, carbohydrate-binding peptides were rationally designed against the glycan polysialic acid (PSA), which appears in many interesting contexts, such as influencing nervous system development on neural progenitor cells and promoting tumor cell metastasis. The rational design approach employed through examination of PSA–protein interactions enabled molecular-level understanding of these natural PSA interactions and led to the development of PSA-binding peptides that may be used in biosensing and targeting applications, such as glycan-based targeting of stem cells for regenerative medicine. PSA-binding peptides were shown to demonstrate sequence-dependent specificity, thus leading to the development of rules for glycan recognition by engineered peptide ligands. Ultimately, principles learnt from this body of work may be extended to other carbohydrate systems, leading to such applications as small-molecule targeting of specific glycosylation patterns in healthcare contexts.