Integration of functional peptides into nucleic acid-based nanostructures

Freitag, Jessica S.; Möser, Christin; Belay, Robel; Altattan, Basma; Grasse, Nico; Pothineni, Bhanu Kiran; Schnauß, Jörg; Smith, David M.

doi:10.1039/d2nr05429a

Cited by 4 publications

(1 citation statement)

References 141 publications

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“…The binding was highly dependent on the distance and relative rotation between the two peptides, which could be tuned by adjusting the number of DNA base pairs separating them. Subsequent work demonstrated that DNA duplexes could scaffold two or more binding groups (including peptides, Fab domains, small molecules, or carbohydrates) to enhance binding through multivalent interactions 9 .…”

Section: Introductionmentioning

confidence: 99%

High-affinity binding to the SARS-CoV-2 spike trimer by a nanostructured, trivalent protein-DNA synthetic antibody

Xu,

Zheng,

Prasad

et al. 2023

Preprint

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Multivalency enables nanostructures to bind molecular targets with high affinity. Although antibodies can be generated against a wide range of antigens, their shape and size cannot be tuned to match a given target. DNA nanotechnology provides an attractive approach for designing customized multivalent scaffolds due to the addressability and programmability of the nanostructure shape and size. Here, we design a nanoscale synthetic antibody (“nano-synbody”) based on a three-helix bundle DNA nanostructure with one, two, or three identical arms terminating in a mini-binder protein that targets the SARS-CoV-2 spike protein. The nano-synbody was designed to match the valence and distance between the three receptor binding domains (RBDs) in the spike trimer, in order to enhance affinity. The protein-DNA nano-synbody shows tight binding to the wild-type, Delta, and several Omicron variants of the SARS-CoV-2 spike trimer, with affinity increasing as the number of arms increases from one to three. The effectiveness of the nano-synbody was also verified using a pseudovirus neutralization assay, with the three-arm nanostructure inhibiting two Omicron variants against which the structures with only one or two arms are ineffective. The structure of the three-arm nano-synbody bound to the Omicron variant spike trimer was solved by negative-stain transmission electron microscopy reconstruction, and shows the protein-DNA nanostructure with all three arms attached to the RBD domains, confirming the intended trivalent attachment. The ability to tune the size and shape of the nano-synbody, as well as its potential ability to attach two or more different binding ligands, will enable the high-affinity targeting of a range of proteins not possible with traditional antibodies.

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Section: Introductionmentioning

confidence: 99%

High-affinity binding to the SARS-CoV-2 spike trimer by a nanostructured, trivalent protein-DNA synthetic antibody

Xu,

Zheng,

Prasad

et al. 2023

Preprint

View full text Add to dashboard Cite

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A Multivalent DNA Nanoparticle/Peptide Hybrid Molecular Modality for the Modulation of Protein–Protein Interactions in the Tumor Microenvironment

Roman,

Girgis,

Prisby

et al. 2024

Advanced NanoBiomed Research

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Despite success in the treatment of some blood cancers and melanoma, positive response to immunotherapies remains disappointingly low in the treatment of solid tumors. The context of the molecular crosstalk within the tumor microenvironment can result in dysfunctional immune cell activation, leading to tumor tolerance and progression. Although modulating these protein–protein interactions (PPIs) is vital for appropriate immune cell activation and recognition, targeting nonenzymatic PPIs has proven to be fraught with challenges. To address this, a synthetic, multivalent molecular modality comprised of small interfering peptides precisely hybridized to a semirigid DNA scaffold is introduced. Herein, a prototype of this modality that targets the IL‐33/ST2 signaling axis, which is associated with tumor tolerance and immunotherapy treatment failure is described. Using peptides that mimic the specific high‐energy “hotspot” residues with which the IL‐33/ST2 coreceptor, IL‐1RAcP, interacts with the initial binary complex, this platform is shown to effectively bind IL‐33/ST2 with a KD of 110 nm. Additionally, this molecule effectively abrogates signal transduction in cell models at high nanomolar concentrations and is exquisitely selective for this complex over structurally similar PPIs within the same cytokine superfamily.

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Peptide spiders are emerging as novel therapeutic interventions for nucleic acid delivery

Rahman,

Sahoo,

Almalki

et al. 2024

Drug Discovery Today

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Integration of functional peptides into nucleic acid-based nanostructures

Abstract: In many applications such as diagnostics and therapy development, small peptide fragments consisting of only a few amino acids are often attractive alternatives to bulky proteins. This is due to...

Cited by 4 publications

References 141 publications

High-affinity binding to the SARS-CoV-2 spike trimer by a nanostructured, trivalent protein-DNA synthetic antibody

High-affinity binding to the SARS-CoV-2 spike trimer by a nanostructured, trivalent protein-DNA synthetic antibody

A Multivalent DNA Nanoparticle/Peptide Hybrid Molecular Modality for the Modulation of Protein–Protein Interactions in the Tumor Microenvironment

Peptide spiders are emerging as novel therapeutic interventions for nucleic acid delivery

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