Influence of Sulfur-Containing Diamino Acid Structure on Covalently Crosslinked Copolypeptide Hydrogels

Area of Science:

• Biomaterials Science
• Polymer Chemistry
• Organic Synthesis

Background:

• Biologically relevant non-canonical di-α-amino acids offer unique structural properties.
• Covalently crosslinked polypeptide hydrogels are promising biomaterials.
• Tuning crosslinker chemistry is crucial for controlling hydrogel properties.

Purpose of the Study:

• To synthesize novel di-N-carboxyanhydride (di-NCA) monomers from non-canonical di-α-amino acids.
• To investigate the copolymerization of these di-NCAs with tert-butyl-l-glutamate NCA for hydrogel formation.
• To evaluate the impact of different di-α-amino acid crosslinkers on hydrogel properties and chemical stability.

Main Methods:

• Synthesis of five distinct di-NCA monomers.
• Copolymerization of di-NCAs with tert-butyl-l-glutamate NCA.
• Characterization of resulting polypeptide hydrogels, including crosslinker density and mechanical properties.
• Assessment of hydrogel stability under reductive conditions.

Main Results:

• Di-NCA monomers were synthesized in good yields and high purity.
• Copolymerization yielded covalently crosslinked polypeptide hydrogels with tunable crosslinker densities.
• Hydrogel properties varied significantly based on the specific di-α-amino acid used, with l-cystine forming weaker networks than l-homocystine, l-cystathionine, and l-lanthionine.
• Disulfide crosslinks (from l-cystine) were reducible, while thioether crosslinks (from l-homocystine, l-cystathionine, l-lanthionine) were stable to reduction.

Conclusions:

• Non-canonical di-α-amino acids are viable precursors for di-NCA monomers for polypeptide hydrogel synthesis.
• The choice of di-α-amino acid significantly influences hydrogel network formation and mechanical strength.
• The chemical nature of the crosslinker (disulfide vs. thioether) dictates the hydrogel's response to reduction, offering a pathway for designing stimuli-responsive biomaterials.