Self-Assembled Nanostructures Regulate H2S Release from Constitutionally Isomeric Peptides.

We report here on three constitutionally isomeric peptides, each of which contains two glutamic acid residues and two lysine residues functionalized with S-aroylthiooximes (SATOs), termed peptide-H2S donor conjugates (PHDCs). SATOs decompose in the presence of cysteine to generate hydrogen sulfide (H2S), a biological signaling gas with therapeutic potential. The PHDCs self-assemble in aqueous solution into different morphologies, two into nanoribbons of different dimensions and one into a rigid nanocoil. The rate of H2S release from the PHDCs depends on the morphology, with the nanocoil-forming PHDC exhibiting a complex release profile driven by morphological changes promoted by SATO decomposition. The nanocoil-forming PHDC mitigated the cardiotoxicity of doxorubicin more effectively than its nanoribbon-forming constitutional isomers as well as common H2S donors. This strategy opens up new avenues to develop H2S-releasing biomaterials and highlights the interplay between structure and function from the molecular level to the nanoscale.