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

ABSTRACT: 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.

SUBMITTER: Wang Y

PROVIDER: S-EPMC6225339 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Wang Yin Y Kaur Kuljeet K Scannelli Samantha J SJ Bitton Ronit R Matson John B JB

Journal of the American Chemical Society 20181027 44

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 ...[more]

PMID: 30369241

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Project description:Synthetic nucleic acids have shown great potential in the treatment of various diseases. Nevertheless, the selective delivery to a target tissue has proved challenging. The coupling of nucleic acids to targeting peptides, proteins, and antibodies has been explored as an approach for their selective tissue delivery. Nevertheless, the preparation of covalently coupled peptides and proteins that can also undergo intracellular release as well as deliver more than one copy of the nucleic acid has proved challenging. Recently, we have developed a novel method for the rapid noncovalent conjugation of nucleic acids to targeting single chain antibodies (scFv) using chemically self-assembled nanostructures (CSANs). CSANs have been prepared by the self-assembly of two dihydrofolate reductase molecules (DHFR(2)) and a targeting scFv in the presence of bis-methotrexate (bis-MTX). The valency of the nanorings can be tuned from one to eight subunits, depending on the length and composition of the linker between the dihydrofolate reductase molecules. To explore their potential for the therapeutic delivery of nucleic acids as well as the ability to expand the capabilities of CSANs by incorporating smaller cyclic targeting peptides, we prepared DHFR(2) proteins fused through a flexible peptide linker to cyclic-RGD, which targets ?v?3 integrins, and a bis-MTX chemical dimerizer linked to an antisense oligonucleotide (bis-MTX-ASO) that has been shown to silence expression of eukaryotic translation initiation factor 4E (eIF4E). Monomeric and multimeric cRGD-CSANs were then prepared with bis-MTX-ASO and shown to undergo endocytosis in the breast cancer cell line, MDA-MB-231, which overexpresses ?v?3. The bis-MTX-ASO was shown to undergo endosomal escape resulting in the knock down of eIF4E with at least the same efficiency as ASO delivered by oligofectamine. The modularity, flexibility, and common method of conjugation may prove to be a useful general approach for the targeted delivery of ASOs, as well as other nucleic acids to cells.

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

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Self-Assembled Nanostructures Regulate H<sub>2</sub>S Release from Constitutionally Isomeric Peptides.

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