The Unexpected Advantages of Using D-Amino Acids for Peptide Self- Assembly into Nanostructured Hydrogels for Medicine

Abstract

Self-assembled peptide hydrogels have brought innovation to the medicinal field, not only as responsive biomaterials but also as nanostructured therapeutic agents or as smart drug delivery systems. D-amino acids are typically introduced to increase the peptide enzymatic stability. However, there are several reports of unexpected effects on peptide conformation, self-assembly behavior, cytotoxicity and even therapeutic activity. This mini-review discusses all the surprising twists of heterochiral self-assembled peptide hydrogels, and delineates emerging key findings to exploit all the benefits of D-amino acids in this novel medicinal area.

Fig. (1)

Examples of peptide secondary conformation. Adapted from ref. [3] with kind permission from The Royal Society of Chemistry.

Fig. (2)

Circular dichroism (CD) spectra of heterochiral Phe-Phe-Val tripeptides reveal that chirality of supramolecular arrangements is dictated by the stereoconfiguration of the central amino acid. A) ^LPhe-^LPhe-^LVal (black line) and ^DPhe-^DPhe-^DVal (dotted line) enantiomers; (B) ^DPhe-^LPhe-^LVal (black line) and ^LPhe-^DPhe-^DVal (dotted line) enantiomers; (C) ^DPhe-^LPhe-^DVal (black line) and ^LPhe-^DPhe-^LVal (dotted line) enantiomers; (D) ^LPhe-^LPhe-^DVal (black line) and ^DPhe-^DPhe-^LVal (dotted line) enantiomers. Reprinted from ref. [33] with kind permission of The Royal Society of Chemistry.

Fig. (3)

Ala-Ala dipeptide amphiphiles form helical nanoribbons with a handedness dictated by chirality of the C-terminal amino acid, as observed by AFM. A. left-handed nanoribbons. B. right-handed nanoribbons. Adapted with permission from ref. [38]. Copyright © 2013 American Chemical Society.

Fig. (4)

An equimolar mixture of two self-assembling peptide enantiomers can give rise to A. mixed fibrils, each containing both peptides, or B. self-sorted fibrils, each containing one peptide only. Adapted with permission from ref. [40]. Copyright © 2011 American Chemical Society.

Fig. (5)

Antibacterial activity of self-assembling ^DLeu-^LPhe-^LPhe peptide gel alone (i.e., control, top half of agar plates) or co-assembled with antibiotic ciprofloxacin (i.e., CIP, bottom half of agar plates). Reprinted from ref. [45] Copyright © 2013 with permission from Elsevier.

Fig. (6)

Promising lead candidate to inhibit Aβ peptide aggregation [35].

Fig. (7)

Heterochiral peptide derivative with a thrombin cleavage site (indicated by the scissors) to release a self-assembling gelator [42].

Fig. (8)

Heterochiral self-assembling peptides ^DPhe-^LPhe-^LVal (i.e., fFV) and ^LPhe-^DPhe-^DVal (i.e., Ffv) perform equally well in cytotoxicity tests both in solution (left) and as gels (right). Circles indicate spreading cells. Scale bar = 50 µm. Adapted from ref. [33] with kind permission of The Royal Society of Chemistry.