Tailoring Biomaterials by Tuning Specific Peptide Interactions via Stereochemistry-Directed Interactions and Polymer-Peptide Conjugation 111 views

The complex, dynamic nature of native tissues requires next-generation biomaterials that are highly tunable and robust to address current engineering problems. Peptides are common key components of biomaterials as they undergo specific interactions that can be tailored by a wide sequence design space, but peptides are limited by a lack of in vivo stability. To overcome this instability and expand the tunability of biomaterials, we leveraged stereochemistry-directed interactions and polymer-peptide conjugation as tools to increase peptide stability and modulate specific interactions. In this thesis, we investigated the specific interactions of several peptides as therapeutics and biomaterials and expanded on the design rules that govern stereochemistry-directed interactions and polymer-peptide conjugate biomaterials. In Chapter 2, we utilized photochemistry and the specific, yet displaceable interactions between coiled coil peptides to develop a biomaterial with user-defined, spatiotemporal control over the presentation of biomolecules on the surface. Uniting specific coiled coil interactions with the benefits of stereochemistry-directed interactions, in Chapter 3 we demonstrated that stereochemistry-directed interactions between coiled coils yields complexes that possess greater binding strength and are more enzymatically stable than analogous coiled coils composed of only L-peptides. In Chapter 4 we further employed stereochemistry-directed interactions in the design of polymer-peptide conjugate biomaterials to disperse and prevent aggregates of toxic proteins implicated in amyotrophic lateral sclerosis (ALS), where both D- and L-conjugates successfully dispersed aggregates of a model toxic protein. To target another class of highly charged toxic proteins implicated in ALS, in Chapter 5 we designed a set of peptides to interact electrostatically with these proteins and characterized their interactions using isothermal titration calorimetry to select candidates for conjugation to polymers as polymer-peptide therapeutics. Together, these studies enhance the tunability and functionality of biomaterials by leveraging specific peptide interactions and expanding the design rules for stereochemistry-directed interactions and polymer-peptide conjugates.

PHD (Doctor of Philosophy)

Biomaterials; Stereochemistry-directed interactions; Polymer-peptide conjugates; Tunability

English

2024-12-12