Halogen bonding as a key interaction in the self‐assembly of iodinated diphenylalanine peptides

Pizzi, Andrea; Catalano, Luca; Demitri, Nicola; Dichiarante, Valentina; Terraneo, Giancarlo; Metrangolo, Pierangelo

doi:10.1002/pep2.24127

Cited by 16 publications

(44 citation statements)

References 54 publications

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“… 46 This is in marked contrast with l -(4-I)-Phe- l -Phe and l -(4-I)-Phe- l -(4-I)-Phe crystal structure, where iodine atoms engaged in halogen bonding, yet no gel was formed. 29 However, examples of amyloidogenic short peptides with (4-I)-Phe not engaging in halogen bonding were also described, whereby peptides stacked with their backbones perpendicular to the long axis of the assemblies growth, similarly to compound 6 ( Figure 6 D). 26 , 30 …”

Section: Resultsmentioning

confidence: 99%

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Heterochirality and Halogenation Control Phe-Phe Hierarchical Assembly

et al. 2020

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Diphenylalanine is an amyloidogenic building block that can form a versatile array of supramolecular materials. Its shortcomings, however, include the uncontrolled hierarchical assembly into microtubes of heterogeneous size distribution and well-known cytotoxicity. This study rationalized heterochirality as a successful strategy to address both of these pitfalls and it provided an unprotected heterochiral dipeptide that self-organized into a homogeneous and optically clear hydrogel with excellent ability to sustain fibroblast cell proliferation and viability. Substitution of one l -amino acid with its d -enantiomer preserved the ability of the dipeptide to self-organize into nanotubes, as shown by single-crystal XRD analysis, whereby the pattern of electrostatic and hydrogen bonding interactions of the backbone was unaltered. The effect of heterochirality was manifested in subtle changes in the positioning of the aromatic side chains, which resulted in weaker intermolecular interactions between nanotubes. As a result, d -Phe- l -Phe self-organized into homogeneous nanofibrils with a diameter of 4 nm, corresponding to two layers of peptides around a water channel, and yielded a transparent hydrogel. In contrast with homochiral Phe-Phe stereoisomer, it formed stable hydrogels thermoreversibly. d -Phe- l -Phe displayed no amyloid toxicity in cell cultures with fibroblast cells proliferating in high numbers and viability on this biomaterial, marking it as a preferred substrate over tissue-culture plastic. Halogenation also enabled the tailoring of d -Phe- l -Phe self-organization. Fluorination allowed analogous supramolecular packing as confirmed by XRD, thus nanotube formation, and gave intermediate levels of bundling. In contrast, iodination was the most effective strategy to augment the stability of the resulting hydrogel, although at the expense of optical transparency and biocompatibility. Interestingly, iodine presence hindered the supramolecular packing into nanotubes, resulting instead into amphipathic layers of stacked peptides without the occurrence of halogen bonding. By unravelling fine details to control these materials at the meso- and macro-scale, this study significantly advanced our understanding of these systems.

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Section: Resultsmentioning

confidence: 99%

“…Phe-Phe gave rise to metastable hydrogels that underwent syneresis over time, 27 , 28 and N-terminal halogenation was shown to affect self-assembly, so that the poorly water-soluble l -(4-I)-Phe- l -Phe and l -(4-I)-Phe- l -(4-I)-Phe were reported to form crystals. 29 …”

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confidence: 99%

Heterochirality and Halogenation Control Phe-Phe Hierarchical Assembly

et al. 2020

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“…18–21 Halogenation is another useful strategy, which has the additional advantage of enabling further non-covalent interactions. 20,22,23 Amino acid chirality is also emerging as a strategy to control dipeptide self-assembly, with heterochirality resulting in increased hydrophobicity, as shown in dipeptides bearing Leu/Ile and Phe amino acids. 24,25…”

Section: Introductionmentioning

confidence: 99%

Single-atom substitution enables supramolecular diversity from dipeptide building blocks

et al. 2022

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“…[5][6][7] In this context, different classes of peptides (including cyclic peptides, 8 ultra-short sequences, 9 and amphiphilic peptide-polymer derivatives 10 ) have been proposed as native building blocks for generating nanostructured aggregates. Peptide-based supramolecular systems showed a wide morphological heterogeneity, including fibers, 11 ribbons, 12 nanorods, 13 films, 14 and nanospheres. 15 Moreover, the possibility of modifying the primary sequence of these building blocks with non-coded amino acids or decorating them with drugs or fluorophores allows to hugely expand the number of potential application areas.…”

Section: Introductionmentioning

confidence: 99%

Peptide‐based hydrogels as delivery systems for doxorubicin

Diaferia

Rosa

Accardo

et al. 2021

Journal of Peptide Science

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Hydrogels (HGs) and nanogels (NGs) have been recently identified as innovative supramolecular materials for many applications in biomedical field such as in tissue engineering, optoelectronic, and local delivery of active pharmaceutical ingredients (APIs). Due to their in vivo biocompatibility, synthetic accessibility, low cost, and tunability, peptides have been used as suitable building blocks for preparation of HGs and NGs formulations. Peptide HGs have shown an outstanding potential to deliver small drugs, protein therapeutics, or diagnostic probes, maintaining the efficacy of their loaded molecules, preventing degradation phenomena, and responding to external physicochemical stimuli. In this review, we discuss the possible use of peptidebased HGs and NGs as vehicles for the delivery of the anticancer drug doxorubicin (Dox). This anthracycline is clinically used for leukemia, stomach, lung, ovarian, breast, and bladder cancer therapy. The loading of Dox into supramolecular systems (liposomes, micelles, hydrogels, and nanogels) allows reducing its cardiotoxicity.According to a primary sequence classification of the constituent peptide, doxorubicin-loaded systems are here classified in short and ultra-short peptide-based HGs, RGD, or RADA-peptide-based HGs and peptide-based NGs.

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Halogen bonding as a key interaction in the self‐assembly of iodinated diphenylalanine peptides

Cited by 16 publications

References 54 publications

Heterochirality and Halogenation Control Phe-Phe Hierarchical Assembly

Heterochirality and Halogenation Control Phe-Phe Hierarchical Assembly

Single-atom substitution enables supramolecular diversity from dipeptide building blocks

Peptide‐based hydrogels as delivery systems for doxorubicin

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