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Self-Assembly, Tunable Hydrogel Properties, and Selective Anti-Cancer Activity of a Carnosine-Derived Lipidated Peptide.

ABSTRACT: A novel lipopeptide C16KTT?AH was designed that incorporates the KTT tripeptide sequence from "Matrixyl" lipopeptides along with the bioactive ?AH (?-alanine-histidine) carnosine dipeptide motif, attached to a C16 hexadecyl lipid chain. We show that this peptide amphiphile self-assembles above a critical aggregation concentration into ?-sheet nanotape structures in water, phosphate-buffered saline (PBS), and cell culture media. Nanotape bundle structures were imaged in PBS, the bundling resulting from nanotape associations because of charge screening in the buffer. In addition, hydrogelation was observed and the gel modulus was measured in different aqueous media conditions, revealing tunable hydrogel modulus depending on the concentration and nature of the aqueous phase. Stiff hydrogels were observed by direct dissolution in PBS, and it was also possible to prepare hydrogels with unprecedented high modulus from low-concentration solutions by injection of dilute aqueous solutions into PBS. These hydrogels have exceptional stiffness compared to previously reported ?-sheet peptide-based materials. In addition, macroscopic soft threads which contain aligned nematic structures can be drawn from concentrated aqueous solutions of the lipopeptides. The anti-cancer activity of the lipopeptide was assessed using two model breast cancer cell lines compared to two fibroblast cell line controls. These studies revealed selective concentration-dependent cytotoxicity against MCF-7 cancer cells in the mM concentration range. It was shown that this occurs below the onset of lipopeptide aggregation (i.e., below the critical aggregation concentration), indicating that the cytotoxicity is not related to self-assembly but is an intrinsic property of C16KTT?AH. Finally, hydrogels of this lipopeptide demonstrated slow uptake and release of the Congo red dye, a model diagnostic compound.

SUBMITTER: Castelletto V

PROVIDER: S-EPMC7007010 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Self-Assembly, Tunable Hydrogel Properties, and Selective Anti-Cancer Activity of a Carnosine-Derived Lipidated Peptide.

Castelletto Valeria V Edwards-Gayle Charlotte J C CJC Greco Francesca F Hamley Ian W IW Seitsonen Jani J Ruokolainen Janne J

ACS applied materials & interfaces 20190903 37

A novel lipopeptide C<sub>16</sub>KTTβAH was designed that incorporates the KTT tripeptide sequence from "Matrixyl" lipopeptides along with the bioactive βAH (β-alanine-histidine) carnosine dipeptide motif, attached to a C<sub>16</sub> hexadecyl lipid chain. We show that this peptide amphiphile self-assembles above a critical aggregation concentration into β-sheet nanotape structures in water, phosphate-buffered saline (PBS), and cell culture media. Nanotape bundle structures were imaged in PBS, ...[more]

PMID: 31407889

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Project description:The characterization of self-assembling molecules presents significant experimental challenges, especially when associated with phase separation or precipitation. Transparent window infrared (IR) spectroscopy leverages site-specific probes that absorb in the "transparent window" region of the biomolecular IR spectrum. Carbon-deuterium (C-D) bonds are especially compelling transparent window probes since they are non-perturbative, can be readily introduced site selectively into peptides and proteins, and their stretch frequencies are sensitive to changes in the local molecular environment. Importantly, IR spectroscopy can be applied to a wide range of molecular samples regardless of solubility or physical state, making it an ideal technique for addressing the solubility challenges presented by self-assembling molecules. Here, we present the first continuous observation of transparent window probes following stopped-flow initiation. To demonstrate utility in a self-assembling system, we selected the MAX1 peptide hydrogel, a biocompatible material that has significant promise for use in drug delivery and medical applications. C-D labeled valine was synthetically introduced into five distinct positions of the twenty-residue MAX1 β-hairpin peptide. Consistent with current structural models, steady-state IR absorption frequencies and linewidths of C-D bonds at all labeled positions indicate that these side chains occupy a hydrophobic region of the hydrogel and that the motion of side chains located in the middle of the hairpin is more restricted than those located on the hairpin ends. Following a rapid change in ionic strength to initiate self-assembly, the peptide absorption spectra were monitored as function of time, allowing determination of site-specific time constants. We find that within the experimental resolution, MAX1 self-assembly occurs as a cooperative process. These studies suggest that stopped-flow transparent window FTIR can be extended to other time-resolved applications, such as protein folding and enzyme kinetics.

Dataset Information

Self-Assembly, Tunable Hydrogel Properties, and Selective Anti-Cancer Activity of a Carnosine-Derived Lipidated Peptide.

Publications

Self-Assembly, Tunable Hydrogel Properties, and Selective Anti-Cancer Activity of a Carnosine-Derived Lipidated Peptide.

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