Biomedical Applications of Self-Assembling Peptides

Rad‐Malekshahi, Mazda; Lempsink, L.J.R.; Amidi, Maryam; Hennink, Wim E.; Mastrobattista, Enrico

doi:10.1021/acs.bioconjchem.5b00487

Cited by 145 publications

(137 citation statements)

References 137 publications

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“…Nanofibers enabled by symmetric design owe their extraordinary stability solely to the sticky-ended association of peptides, and yield extended human-scale triple-helices. Although the self-assembly “alphabet” available for CMP-based nanostructures is crude in comparison with DNA/RNA, the ease of their interfacing with both biology 9,38 and nanotechnology 16,39 encourage their development.…”

Section: Discussionmentioning

confidence: 99%

Peptide tessellation yields micrometre-scale collagen triple helices

et al. 2016

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Sticky-ended DNA duplexes can associate spontaneously into long double helices; however, such self-assembly is much less developed with proteins. Collagen is the most prevalent component of the extracellular matrix and a common clinical biomaterial. Like natural DNA, the ∼103-residue triple-helices (∼300 nm) of natural collagen are recalcitrant to chemical synthesis. Here we show how the self-assembly of short collagen-mimetic peptides (CMPs) can enable the fabrication of synthetic collagen triple-helices that are nearly a micron in length. Inspired by the mathematics of tessellations, we derive rules for the design of single CMPs that self-assemble into long triple helices with perfect symmetry. Sticky-ends thus created are uniform across the assembly and drive its growth. Enacting this design yields individual triple-helices that match or exceed those in natural collagen in length and are remarkably thermostable, despite the absence of higher-order association. Symmetric assembly of CMPs provides an enabling platform for the development of advanced materials for medicine and nanotechnology.

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Section: Discussionmentioning

confidence: 99%

Peptide tessellation yields micrometre-scale collagen triple helices

et al. 2016

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“…The naturally biodegradable self-assembling peptide systems are extensively investigated as biomaterials for tissue engineering, drug delivery, and vaccination [6, 7]. The versatility of these biomaterials relies on the precise and flexible design of unit peptide building blocks and often requires specific conditions for self-assembly and stability.…”

Section: Introductionmentioning

confidence: 99%

“…The versatility of these biomaterials relies on the precise and flexible design of unit peptide building blocks and often requires specific conditions for self-assembly and stability. A majority of reported self-assembled peptides adopt a β-sheet secondary structure and form into long-range ordered nanofibers, which at high concentrations can produce hydrogels [6]. Amongst these, RADA16-I is a classic self-assembling β-sheet peptide and is commercially available (PuraMatrix™) for biomedical research and pre-clinical applications [6, 8].…”

Section: Introductionmentioning

confidence: 99%

Rational design of charged peptides that self-assemble into robust nanofibers as immune-functional scaffolds

et al. 2017

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Self-assembling peptides programed by sequence design to form predefined nanostructures are useful for a variety of biomedical applications. However, assemblies of classic ionic self-complementary peptides are unstable in neutral pH, while charged peptide hydrogels have low mechanical strength. Here, we report on the rational design of a self-assembling peptide system with optimized charge distribution and density for bioscaffold development. Our designer peptides employs a sequence pattern that undergoes salt triggered self-assembly into β-sheet rich cationic nanofibers in the full pH range (pH 0 to 14). Our peptides form nanofibrils in physiological condition at a minimum concentration that is significantly lower than has been reported for self-assembly of comparable peptides. The robust fiber-forming ability of our peptides results in the rapid formation of hydrogels in physiological conditions with strong mechanical strength. Moreover, fiber structure is maintained even upon dense conjugation with a model bioactive cargo OVA257–264 peptide. Nanofibers carrying OVA257–264 significantly enhanced CD8+ T cell activation in vitro. Subcutaneous immunization of our peptide fiber vaccine also elicited robust CD8+ T cell activation and proliferation in vivo. Our self-assembling peptides are expected to provide a versatile platform to construct diverse biomaterials.

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“…29 Increasing the GLU residues at the C-terminus of SA2 from 2 to 7 did not change the overall structure of SA2 vesicle. 30, 31 Thus, the difference in the peptide orientation in SA2 and BAP assemblies is not likely due to different head-tail ratios and are more likely a result of the peptide sequences. 30 As showed in the self-assembly simulation of BAP, the PHE/CHA clusters formed during the early stages of aggregation, would make a parallel/tail-to-tail orientation more favored.…”

Section: Resultsmentioning

confidence: 99%

“…30, 31 Thus, the difference in the peptide orientation in SA2 and BAP assemblies is not likely due to different head-tail ratios and are more likely a result of the peptide sequences. 30 As showed in the self-assembly simulation of BAP, the PHE/CHA clusters formed during the early stages of aggregation, would make a parallel/tail-to-tail orientation more favored. As the PHE cluster kept growing during the assembling of small clusters, the preference of parallel orientation is preserved in the final vesicle structure.…”

Section: Resultsmentioning

confidence: 99%

Organization and Structure of Branched Amphipathic Oligopeptide Bilayers

et al. 2016

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A class of self-assembling Branched Amphiphilic Peptide Capsules (BAPCs) was recently developed that could serve as a new drug delivery vehicle. BAPCs can encapsulate solutes up to ~12 kDa during assembly, are unusually stable and readily taken up by cells with low cytotoxicity. Coarse-grained simulations have supported that BAPCs are defined by bilayers that resemble those formed by diacyl-phospholipids. Here, atomistic simulations were performed to characterize the structure and organization of bilayers formed by three branched amphiphilic peptides (BAPs), bis(Ac-FLIVIGSII)-K-K4-CO-NH2, bis(Ac-CHA-LIVIGSII)-K-K4-CO-NH2, and bis(Ac-FLIVI)-K-K4-CO-NH2, respectively. The results show BAPs form a network of intra- and intermolecular backbone hydrogen bonds within the same leaflet in addition to hydrophobic sidechain interactions. The terminal residues of two leaflets form an interdigitation region locking two leaflets together. The phenyl groups in bis(Ac-FLIVIGSII)-K-K4-CO-NH2 and bis(Ac-FLIVI)-K-K4-CO-NH2 are tightly packed near the bilayer center, but do not formed ordered structures with specific π-π stacking. Replacing phenyl groups with the cyclo-hexane sidechain only slightly increases the level of disorder in bilayer structures, and thus should not significantly affect the stability, consistent with experimental results on bis(Ac-CHA-LIVIGSII)-K-K4-CO-NH2 BAPCs. Self-assembly simulations further suggest that leaflet interdigitation likely occurs at early stages of BAPC formation. Atomistic simulations also reveal that the BAPC bilayers are highly permeable to water. This prediction was validated using fluorescence measurements of encapsulated self-quenching dye upon transferring BAPCs to buffers with different salt concentrations. Improved understanding of the organization and structure of BAPC bilayers at atomic level will provide a basis for future rational modifications of BAP sequence to improve BAPC properties as a new class of delivery vehicle.

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Biomedical Applications of Self-Assembling Peptides

Cited by 145 publications

References 137 publications

Peptide tessellation yields micrometre-scale collagen triple helices

Peptide tessellation yields micrometre-scale collagen triple helices

Rational design of charged peptides that self-assemble into robust nanofibers as immune-functional scaffolds

Organization and Structure of Branched Amphipathic Oligopeptide Bilayers

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