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Dehydropeptide Supramolecular Hydrogels and Nanostructures As Potential Peptidomimetic Biomedical Materials

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Dehydropeptide Supramolecular Hydrogels and Nanostructures As Potential Peptidomimetic Biomedical Materials International Journal of Molecular Sciences Review Dehydropeptide Supramolecular Hydrogels and Nanostructures as Potential Peptidomimetic Biomedical Materials Peter J. Jervis * , Carolina Amorim, Teresa Pereira, José A. Martins and Paula M. T. Ferreira Centre of Chemistry, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal; [email protected] (C.A.); [email protected] (T.P.); [email protected] (J.A.M.); [email protected] (P.M.T.F.) * Correspondence: [email protected] Abstract: Supramolecular peptide hydrogels are gaining increased attention, owing to their potential in a variety of biomedical applications. Their physical properties are similar to those of the extracel- lular matrix (ECM), which is key to their applications in the cell culture of specialized cells, tissue engineering, skin regeneration, and wound healing. The structure of these hydrogels usually consists of a di- or tripeptide capped on the N-terminus with a hydrophobic aromatic group, such as Fmoc or naphthalene. Although these peptide conjugates can offer advantages over other types of gelators such as cross-linked polymers, they usually possess the limitation of being particularly sensitive to proteolysis by endogenous proteases. One of the strategies reported that can overcome this barrier is to use a peptidomimetic strategy, in which natural amino acids are switched for non-proteinogenic analogues, such as D-amino acids, β-amino acids, or dehydroamino acids. Such peptides usually possess much greater resistance to enzymatic hydrolysis. Peptides containing dehydroamino acids, Citation: Jervis, P.J.; Amorim, C.; i.e., dehydropeptides, are particularly interesting, as the presence of the double bond also intro- Pereira, T.; Martins, J.A.; Ferreira, duces a conformational restraint to the peptide backbone, resulting in (often predictable) changes P.M.T. Dehydropeptide Supramolecular to the secondary structure of the peptide. This review focuses on peptide hydrogels and related Hydrogels and Nanostructures as nanostructures, where α,β-didehydro-α-amino acids have been successfully incorporated into the Potential Peptidomimetic Biomedical Materials. Int. J. Mol. Sci. 2021, 22, structure of peptide hydrogelators, and the resulting properties are discussed in terms of their po- 2528. https://doi.org/10.3390/ijms tential biomedical applications. Where appropriate, their properties are compared with those of 22052528 the corresponding peptide hydrogelator composed of canonical amino acids. In a wider context, we consider the presence of dehydroamino acids in natural compounds and medicinally important Academic Editor: Bice Conti compounds as well as their limitations, and we consider some of the synthetic strategies for obtaining dehydropeptides. Finally, we consider the future direction for this research area. Received: 2 February 2021 Accepted: 25 February 2021 Keywords: hydrogel; supramolecular; dehydrodipeptide; drug delivery; wound healing; cancer; Published: 3 March 2021 smart materials; peptidomimetic Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- 1. Introduction iations. Dehydroamino acid residues are commonly employed in peptidomimetic medicinal chemistry strategies [1]. Furthermore, they feature in their own right in many naturally occurring peptides and several medicinally important molecules [2–5]. This review summa- rizes the reports of where dehydroamino acid residues have been successfully employed in Copyright: © 2021 by the authors. the development of supramolecular molecular assemblies, including hydrogels, nanoparti- Licensee MDPI, Basel, Switzerland. cles, nanotubes, nanospheres, and other nanostructures. We begin with a general overview This article is an open access article of supramolecular hydrogels and related nanostructures; then, we consider the structure distributed under the terms and conditions of the Creative Commons and properties of dehydroamino acids and how these may influence the assembly of Attribution (CC BY) license (https:// supramolecular structures. creativecommons.org/licenses/by/ 4.0/). Int. J. Mol. Sci. 2021, 22, 2528. https://doi.org/10.3390/ijms22052528 https://www.mdpi.com/journal/ijms Int.Int. J. J. Mol. Mol. Sci. Sci. 20212021, ,2222, ,x 2528 FOR PEER REVIEW 22 of of 19 19 1.1.1.1. Supramolecular Supramolecular Peptide Peptide Hydrogels Hydrogels SupramolecularSupramolecular hydrogels hydrogels consist consist of of non-covalently non-covalently cross-linked cross-linked polymers polymers and and pep- pep- tidestides [6]. [6]. Peptide-based Peptide-based hydrogels hydrogels are are gaining gaining popularity popularity owing owing to to their their intrinsic intrinsic biocom- biocom- patibility.patibility. Short Short peptides peptides attached attached to to an an arom aromaticatic capping capping group group are are pa particularlyrticularly attractive attractive alternativesalternatives as as minimalist minimalist low-molecular low-molecular weight weight gelators gelators [7]. [7]. In In some some specific specific cases, cases, short short peptidespeptides without without an an aromatic aromatic capping capping group group can can form form hydrogels hydrogels [8,9]. [8,9]. The The combination combination ofof intermolecular intermolecular interactions, interactions, such such as as hydrogen hydrogen bonds, bonds, ππ––ππ stacking,stacking, and and van van der der Waals Waals forcesforces allows allows molecular molecular self-assembly self-assembly to to take take place, place, with with the the formation formation of of nanofibrils. nanofibrils. WhenWhen these these nanofibrils nanofibrils are are able able to to trap trap wate waterr molecules, molecules, self-supporting self-supporting soft soft materials, materials, suchsuch as as hydrogels, hydrogels, may may form form [6]. [6]. The The gelation gelation process process is is often often initiated initiated by by means means of of an an externalexternal trigger, trigger, which which lowers lowers the the solubility solubility of of a a hydrogelator hydrogelator in in solution solution [10]. [10]. The The most most commonlycommonly employed employed triggers triggers for for hydrogelation hydrogelation are are the the use use of of a a heating–cooling heating–cooling cycle, cycle, a a pHpH change, change, the addition of chelatingchelating metalmetal ions,ions, aa solvent solvent swap, swap, or or an an enzymatic, enzymatic, chemical, chemi- cal,or photolyticor photolytic cleavage cleavage of a solubilizingof a solubilizing group group (Figure (Figure1A) [ 11 1A)–15 ].[11–15]. A balance A balance of hydrophilic of hy- drophilicand hydrophobic and hydrophobic properties properti is cruciales is to crucial the gelation to the gelation process. process. If a putative If a putative gelator isgela- too torhydrophilic, is too hydrophilic, it may stay it may in aqueous stay in aqueous solution, solution, if it is too if hydrophobic,it is too hydrophobic, then precipitation then pre- cipitationmay occur may before occur the before onset ofthe the onset gelation of the process gelation [16 process]. Generally, [16]. Generally, a clogP value a clogP of between value of3.4 between and 5.5 is3.4 considered and 5.5 is idealconsidered [7]. In additionideal [7]. to In a addition favorable to polarity, a favorable two orpolarity, three aromatic two or threegroups aromatic are usually groups required are usually to promote required the to intramolecular promote the intramolecular stacking [17]. Hydrogels stacking [17]. can Hydrogelsbe characterized can be usingcharacterized a variety using of techniques, a variety includingof techniques, tube including inversion tube tests, inversion rheology, tests,fluorescence rheology, spectroscopy, fluorescence circular spectroscopy, dichroism circular (CD) dichroism spectroscopy, (CD) and spectroscopy, various microscopic and var- ioustechniques microscopic such techniques as scanning such electron as scanning microscopy electron (SEM), microscopy tunneling (SEM), electron tunneling microscopy elec- tron(TEM), microscopy and atomic (TEM), force and microscopy atomic force (AFM) microscopy [18]. (AFM) [18]. FigureFigure 1. 1. (A(A) )Schematic Schematic of of the the formatio formationn of ofpeptide peptide hydrogels. hydrogels. (B) (BiologicalB) Biological applications applications of supramolecular of supramolecular peptide peptide hy- drogels and related nanostructures. (C) Examples of well-studied supramolecular peptide hydrogelators. (D) Some pep- hydrogels and related nanostructures. (C) Examples of well-studied supramolecular peptide hydrogelators. (D) Some tidomimetic strategies in the design of supramolecular hydrogels. peptidomimetic strategies in the design of supramolecular hydrogels. TheThe properties properties of of hydrogels hydrogels often often resemble resemble those those of of the the extracellular extracellular matrix, matrix, and and as as such,such, they they have manymany biomedicalbiomedical applications applications in in tissue tissue engineering, engineering, skin skin regeneration regeneration and andwound wound healing, healing, 3D bioprinting, 3D bioprinting, and biosensors and biosensors [19]. Alongside [19]. Alongside other related other nanostruc- related nanostructures,tures, they are also they promising are also promising materials materi for deliveryals for vehiclesdelivery invehicles sustained in sustained and/or targeted and/or targeteddrug release drug (Figure release1
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