The substitution of a single amino acid with its enantiomer for control over the adjuvant activity of self-assembling peptides

The substitution of a single amino acid with its enantiomer may lead to variations in self-assembled nanostructures and biological functions. In this study, we reported three novel heterochiral peptide hydrogels, Nap-G(D)FFY (gel-1), Nap-GF(D)FY (gel-2) and Nap-GFF(D)Y (gel-3), from Nap-GFFY via the substitution of a single amino acid with its enantiomer. We found that the resulting hydrogels possessed diverse self-assembly behaviors and adjuvant activities. Compared to the homochiral l-gel formed from Nap-GFFY, gel-1 was basically similar, gel-2 exhibited a medium improvement in immunocompetence tuning ability, and gel-3 showed the better self-assembly of nanofibers with superior mechanical properties and the ability for slow antigen release. Moreover, the adjuvant effect of gel-3 was prominent, promoting both specific antibody titers and the production of cytokines. Besides, this regulation was more remarkable with respect to enhancing cellular immune responses. Hence, we came to the conclusion in this study that the substitution of a single amino acid with its enantiomer further away from rather than closer to the end-capping group could be important and effective for biofunction regulation. Our study provides a useful strategy for tuning the properties of self-assembling peptides for different biological applications.