A short peptide that preferentially binds c-MYC G-quadruplex DNA

Minard, Aisling; Morgan, Danielle C.; Raguseo, Federica; Porzio, Anna Di; Liano, Denise; Jamieson, Andrew G.; Antonio, Marco Di

doi:10.1039/d0cc02954h

Cited by 29 publications

(46 citation statements)

References 19 publications

(18 reference statements)

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“…Reports of nonplanar molecules interacting with G4s are quite scarce, [18] although in contrast many natural proteins have been identified that interact with G4s, [19] commonly via α‐helical recognition units [20] . In this context we note that certain metallo‐supramolecular helical assemblies, which have similar size, shape, charge, and amphipathic architectures to short cationic α‐helical peptides [21] have been shown also to interact.…”

Section: Introductionmentioning

confidence: 86%

Fe^II Metallohelices Stabilize DNA G‐Quadruplexes and Downregulate the Expression of G‐Quadruplex‐Regulated Oncogenes

Malina

Kostrhunová

Scott

et al. 2021

Chemistry A European J

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DNA G‐quadruplexes (G4s) have been identified within the promoter regions of many proto‐oncogenes. Thus, G4s represent attractive targets for cancer therapy, and the design and development of new drugs as G4 binders is a very active field of medicinal chemistry. Here, molecular biophysics and biology methods were employed to investigate the interaction of chiral metallohelices with a series of four DNA G4s (hTelo, c‐myc, c‐kit1, c‐kit2) that are formed by the human telomeric sequence (hTelo) and in the promoter regions of c‐MYC and c‐KIT proto‐oncogenes. We show that the investigated water‐compatible, optically pure metallohelices, which are made by self‐assembly of simple nonpeptidic organic components around FeII ions and exhibit bioactivity emulating the natural systems, bind with high affinity to G4 DNA and much lower affinity to duplex DNA. Notably, both enantiomers of a metallohelix containing a m‐xylenyl bridge (5 b) were found to effectively inhibit primer elongation catalyzed by Taq DNA polymerase by stabilizing G4 structures formed in the template strands containing c‐myc and c‐kit2 G4‐forming sequences. Moreover, both enantiomers of 5 b downregulated the expression of c‐MYC and c‐KIT oncogenes in human embryonic kidney cells at mRNA and protein levels. As metallohelices also bind alternative nucleic acid structures, they hold promise as potential multitargeted drugs.

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Section: Introductionmentioning

confidence: 86%

Fe^II Metallohelices Stabilize DNA G‐Quadruplexes and Downregulate the Expression of G‐Quadruplex‐Regulated Oncogenes

Malina

Kostrhunová

Scott

et al. 2021

Chemistry A European J

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“…There are many lines of inquiry described elsewhere to derive molecules that indirectly modulate c-Myc by inhibiting the activity of the many upstream and downstream proteins that interact with and impact upon its activity, or that target it for degradation. For example, approaches to target c-Myc indirectly, by binding BRD4, CDK7/9, or G-quadruplex DNA, have been reported and are reviewed elsewhere [ 13 , 48 , 66 – 69 ]. Here we focus on the more desirable but challenging task of inhibiting c-Myc directly.…”

Section: Challenges and Considerations In Targeting C-mycmentioning

confidence: 99%

Taking the Myc out of cancer: toward therapeutic strategies to directly inhibit c-Myc

et al. 2021

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Abstractc-Myc is a transcription factor that is constitutively and aberrantly expressed in over 70% of human cancers. Its direct inhibition has been shown to trigger rapid tumor regression in mice with only mild and fully reversible side effects, suggesting this to be a viable therapeutic strategy. Here we reassess the challenges of directly targeting c-Myc, evaluate lessons learned from current inhibitors, and explore how future strategies such as miniaturisation of Omomyc and targeting E-box binding could facilitate translation of c-Myc inhibitors into the clinic.

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“…In this work, we have utilized PDS for both in vitro, in nuclear cell lysate, and in cell assays, underscoring its versatility and application in studying rG4 in lncRNA. RHAU53 peptide is an emerging G4 targeting tool that can specifically identify parallel G4, and a number of improved versions have been recently developed for specific G4 targeting (72,(89)(90)(91). rG4-targeting L-RNA aptamer is a new class of G4-targeting tool introduced by us (56).…”

Section: Discussionmentioning

confidence: 99%

Identification and targeting of G-quadruplex structures inMALAT1long non-coding RNA

Mou

Liew

Kwok

2021

Preprint

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RNA G-quadruplexes (rG4s) have functional roles in many cellular processes in diverse organisms. While a number of rG4 examples have been reported in coding messenger RNAs (mRNA), so far only limited works have studied rG4s in non-coding RNAs (ncRNAs), especially in long non-coding RNAs (lncRNAs) that are of emerging interest and significance in biology. Herein, we report that MALAT1 lncRNA contains conserved rG4 motifs, forming thermostable rG4 structures with parallel topology. We also show that rG4s in MALAT1 lncRNA can interact with NONO protein with high specificity and affinity in vitro and in nuclear cell lysate, and we provide in vivo data to support that NONO protein recognizes MALAT1 lncRNA via rG4 motifs. Notably, we demonstrate that rG4s in MALAT1 lncRNA can be targeted by rG4-specific small molecule, peptide, and L-aptamer, leading to the dissociation of MALAT1 rG4-NONO protein interaction. Altogether, this study uncovers new and important rG4s in MALAT1 lncRNAs, reveals their specific interactions with NONO protein, offers multiple strategies for targeting MALAT1 and its RNA-protein complex via its rG4 structure, and illustrates the prevalence and significance of rG4s in ncRNAs.

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A short peptide that preferentially binds c-MYC G-quadruplex DNA

Abstract:
G-quadruplexes are nucleic-acids secondary structures that are highly abundant in the human genome. In this work,we identified a short-peptide that displays selectivity for the G-quadruplex formed in the promoter region of the oncogene c-MYC.

Cited by 29 publications

References 19 publications

Fe^II Metallohelices Stabilize DNA G‐Quadruplexes and Downregulate the Expression of G‐Quadruplex‐Regulated Oncogenes

Fe^II Metallohelices Stabilize DNA G‐Quadruplexes and Downregulate the Expression of G‐Quadruplex‐Regulated Oncogenes

Taking the Myc out of cancer: toward therapeutic strategies to directly inhibit c-Myc

Identification and targeting of G-quadruplex structures inMALAT1long non-coding RNA

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A short peptide that preferentially binds c-MYC G-quadruplex DNA

Abstract: G-quadruplexes are nucleic-acids secondary structures that are highly abundant in the human genome. In this work,we identified a short-peptide that displays selectivity for the G-quadruplex formed in the promoter region of the oncogene c-MYC.

Cited by 29 publications

References 19 publications

FeII Metallohelices Stabilize DNA G‐Quadruplexes and Downregulate the Expression of G‐Quadruplex‐Regulated Oncogenes

FeII Metallohelices Stabilize DNA G‐Quadruplexes and Downregulate the Expression of G‐Quadruplex‐Regulated Oncogenes

Taking the Myc out of cancer: toward therapeutic strategies to directly inhibit c-Myc

Identification and targeting of G-quadruplex structures inMALAT1long non-coding RNA

Contact Info

Product

Resources

About

Abstract:
G-quadruplexes are nucleic-acids secondary structures that are highly abundant in the human genome. In this work,we identified a short-peptide that displays selectivity for the G-quadruplex formed in the promoter region of the oncogene c-MYC.

Fe^II Metallohelices Stabilize DNA G‐Quadruplexes and Downregulate the Expression of G‐Quadruplex‐Regulated Oncogenes

Fe^II Metallohelices Stabilize DNA G‐Quadruplexes and Downregulate the Expression of G‐Quadruplex‐Regulated Oncogenes