Stereoselective Self-Assembly of DNA Binding Helicates Directed by the Viral β-Annulus Trimeric Peptide Motif

Gómez‐González, Jacobo; Bouzada, David; Pérez-Márquez, Lidia Ana; Sciortino, Giuseppe; Maréchal, Jean‐Didier; López, Miguel Vázquez; Vázquez, M. Eugenio

doi:10.1021/acs.bioconjchem.1c00312

Cited by 4 publications

(5 citation statements)

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“…15,16 Since the group of Prof. M. Hannon discovered that metal helicates fit into the branching point of 3WJs, 17 researchers have described a number of molecules that exploit symmetry, hydrophobicity, shape and charge complementarity to target such central cavity in 3WJs. 18 Examples include peptide helicates, [19][20][21][22] azacryptands, [23][24][25] triptycenes, 26,27 cationic calix [3]carbazoles, 28 and derivatives with appended peptides for additional nonspecific interactions with the duplex branches. [29][30][31] However, the branching point targeted by these agents is basically a featureless hydrophobic hole that does not present any obvious structural elements to allow the sequence selective recognition of 3WJs.…”

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Selective recognition of A/T-rich DNA 3-way junctions with a three-fold symmetric tripeptide

et al. 2022

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Selective recognition of A/T-rich DNA 3-way junctions with a three-fold symmetric tripeptide

et al. 2022

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“…Monchaud has screened libraries of agents for 3WJ binding and identified as his lead agent an organic 3-arm cryptand-type system with aryl rings that could potentially rotate to present a very similar aryl surface conformation to the cylinders. − Although the binding is not yet structurally characterized, very recent MD simulations suggest this cryptand may also be able to thread into a 3WJ and bind as the cylinder does . Other 3WJ binders ,,,− that lack these outward-facing pi-surfaces are also reportedsome of them may bind at the outside of (rather than within) the junction cavity.…”

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confidence: 99%

Organometallic Pillarplexes That Bind DNA 4-Way Holliday Junctions and Forks

et al. 2023

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Holliday 4-way junctions are key to important biological DNA processes (insertion, recombination, and repair) and are dynamic structures that adopt either open or closed conformations, the open conformation being the biologically active form. Tetracationic metallo-supramolecular pillarplexes display aryl faces about a cylindrical core, an ideal structure to interact with open DNA junction cavities. Combining experimental studies and MD simulations, we show that an Au pillarplex can bind DNA 4-way (Holliday) junctions in their open form, a binding mode not accessed by synthetic agents before. Pillarplexes can bind 3-way junctions too, but their large size leads them to open up and expand that junction, disrupting the base pairing, which manifests in an increased hydrodynamic size and lower junction thermal stability. At high loading, they rearrange both 4-way and 3-way junctions into Y-shaped forks to increase the available junction-like binding sites. Isostructural Ag pillarplexes show similar DNA junction binding behavior but lower solution stability. This pillarplex binding contrasts with (but complements) that of metallo-supramolecular cylinders, which prefer 3-way junctions and can rearrange 4-way junctions into 3-way junction structures. The pillarplexes’ ability to bind open 4-way junctions creates exciting possibilities to modulate and switch such structures in biology, as well as in synthetic nucleic acid nanostructures. In human cells, the pillarplexes do reach the nucleus, with antiproliferative activity at levels similar to those of cisplatin. The findings provide a new roadmap for targeting higher-order junction structures using a metallo-supramolecular approach, as well as expanding the toolbox available to design bioactive junction binders into organometallic chemistry.

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“…[32][33][34][35] Although the binding is not yet structurally characterised, very recent MD simulations suggest this cryptand may also be able to thread into a 3WJ and bind as the cylinder does. 36 Other 3WJ binders 32,34,35,[37][38][39][40][41][42][43][44][45][46] that lack these outward-facing pi-surfaces may bind outside the junction cavity.…”

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confidence: 99%

Organometallic Pillarplexes that bind DNA 4-way Holliday Junctions and Forks

Craig¹,

Melidis²,

Williams³

et al. 2023

Preprint

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Holliday 4-way junctions are key to important biological DNA processes (insertion, recombination and repair) and are dynamic structures which adopt either open or closed conformations, with the open conformation being the biologically active form. Tetracationic metallo-supramolecular pillarplexes display aryl faces about a cylindrical core giving them an ideal structure to interact with the central cavities of open DNA junctions. Combining experimental studies and MD simulations we show that an Au pillarplex can bind DNA 4-way junctions (Holliday junctions) in their open form, a binding mode not accessed by synthetic agents before. The Au pillarplexes can bind designed 3-way junctions too but their large size leads them to open up and expand that junction, disrupting the base pairing which manifests in an increase in hydrodynamic size and a lower junction thermal stability. At high loading they re-arrange both 4-way and 3-way junctions into Y-shaped DNA forks to increase the available junction-like binding sites. The structurally related Ag pillarplexes show similar DNA junction binding behaviour, but a lower solution stability. This pillarplex binding contrasts with (but complements) that of the metallo-supramolecular cylinders, which prefer 3-way junctions and we show can rearrange 4-way junctions into 3-way junction structures. The ability of pillarplexes to bind open 4-way junctions creates exciting possibilities to modulate and switch such structures in biology, as well as in synthetic nucleic acid nanostructures where they are key interconnecting components. Studies in human cells, confirm that the pillarplexes do reach the nucleus, with antiproliferative activity at levels similar to those of cisplatin. The findings provide a new roadmap for targeting higher order junction structures using a metallo-supramolecular approach, as well as expanding the toolbox available to design bioactive junction-binders into organometallic chemistry.

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Stereoselective Self-Assembly of DNA Binding Helicates Directed by the Viral β-Annulus Trimeric Peptide Motif

Cited by 4 publications

References 52 publications

Selective recognition of A/T-rich DNA 3-way junctions with a three-fold symmetric tripeptide

Selective recognition of A/T-rich DNA 3-way junctions with a three-fold symmetric tripeptide

Organometallic Pillarplexes That Bind DNA 4-Way Holliday Junctions and Forks

Organometallic Pillarplexes that bind DNA 4-way Holliday Junctions and Forks

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