Designing stapled peptides to inhibit <scp>protein‐protein</scp> interactions: An analysis of successes in a rapidly changing field

Bluntzer, Marie T. J.; O’Connell, James P.; Baker, Terry; Michel, Julien; Hulme, Alison N.

doi:10.1002/pep2.24191

Cited by 41 publications

(25 citation statements)

References 192 publications

(271 reference statements)

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“…A major limitation of the stapled peptide is its predominant endocytic uptake resulting in high peptide amounts being trapped in endosomes. To transform this first-generation compound into a lead compound, diversification of staple type and position combined with fine-tuning core hydrophobicity and positive net charge is likely to increase cellular uptake and robust bioactivity (37,38). Prominent amino acid substitutions include the incorporation of arginines or arginine derivatives, namely homo-arginine and 4-guanidino-phenylalanine (38).…”

Section: Discussionmentioning

confidence: 99%

A stapled peptide mimetic of the CtIP tetramerization motif interferes with double-strand break repair and replication fork protection

et al. 2021

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Cancer cells display high levels of DNA damage and replication stress, vulnerabilities that could be exploited by drugs targeting DNA repair proteins. Human CtIP promotes homology-mediated repair of DNA double-strand breaks (DSBs) and protects stalled replication forks from nucleolytic degradation, thus representing an attractive candidate for targeted cancer therapy. Here, we establish a peptide mimetic of the CtIP tetramerization motif that inhibits CtIP activity. The hydrocarbon-stapled peptide encompassing amino acid residues 18 to 28 of CtIP (SP18–28) stably binds to CtIP tetramers in vitro and facilitates their aggregation into higher-order structures. Efficient intracellular uptake of SP18–28 abrogates CtIP localization to damaged chromatin, impairs DSB repair, and triggers extensive fork degradation. Moreover, prolonged SP18–28 treatment causes hypersensitivity to DNA-damaging agents and selectively reduces the viability of BRCA1-mutated cancer cell lines. Together, our data provide a basis for the future development of CtIP-targeting compounds with the potential to treat patients with cancer.

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Section: Discussionmentioning

confidence: 99%

A stapled peptide mimetic of the CtIP tetramerization motif interferes with double-strand break repair and replication fork protection

et al. 2021

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“…In the past few years, there has been growing attention to peptides resembling stretches of endogenous proteins from pharmaceutical companies who are eager to explore the therapeutic potential of such peptides. 16 Peptides Figure 1. Model for the antifibrotic actions of a klotho-derived peptide in the kidney.…”

Section: How Does This Study Compare With Prior Studies?mentioning

confidence: 99%

A Klotho-Derived Peptide as a Possible Novel Drug to Prevent Kidney Fibrosis

Isakova

Yanucil

Faul

2022

American Journal of Kidney Diseases

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“…The design principles of interface peptides and the repertoire of technical solutions are detailed in recent reviews [ 44 , 45 , 46 , 47 , 48 , 49 , 50 ]. Optimization of the linear peptides is usually required to increase the binding affinity to the target protein, overcome a number of pharmacodynamic (pharmacokinetic) limitations and unfavorable physicochemical properties that reduce the in vivo efficacy.…”

Section: Current Approaches To the Design Of Interfacial Peptidesmentioning

confidence: 99%

Interfacial Peptides as Affinity Modulating Agents of Protein-Protein Interactions

2022

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The identification of disease-related protein-protein interactions (PPIs) creates objective conditions for their pharmacological modulation. The contact area (interfaces) of the vast majority of PPIs has some features, such as geometrical and biochemical complementarities, “hot spots”, as well as an extremely low mutation rate that give us key knowledge to influence these PPIs. Exogenous regulation of PPIs is aimed at both inhibiting the assembly and/or destabilization of protein complexes. Often, the design of such modulators is associated with some specific problems in targeted delivery, cell penetration and proteolytic stability, as well as selective binding to cellular targets. Recent progress in interfacial peptide design has been achieved in solving all these difficulties and has provided a good efficiency in preclinical models (in vitro and in vivo). The most promising peptide-containing therapeutic formulations are under investigation in clinical trials. In this review, we update the current state-of-the-art in the field of interfacial peptides as potent modulators of a number of disease-related PPIs. Over the past years, the scientific interest has been focused on following clinically significant heterodimeric PPIs MDM2/p53, PD-1/PD-L1, HIF/HIF, NRF2/KEAP1, RbAp48/MTA1, HSP90/CDC37, BIRC5/CRM1, BIRC5/XIAP, YAP/TAZ–TEAD, TWEAK/FN14, Bcl-2/Bax, YY1/AKT, CD40/CD40L and MINT2/APP.

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Designing stapled peptides to inhibit protein‐protein interactions: An analysis of successes in a rapidly changing field

Cited by 41 publications

References 192 publications

A stapled peptide mimetic of the CtIP tetramerization motif interferes with double-strand break repair and replication fork protection

A stapled peptide mimetic of the CtIP tetramerization motif interferes with double-strand break repair and replication fork protection

A Klotho-Derived Peptide as a Possible Novel Drug to Prevent Kidney Fibrosis

Interfacial Peptides as Affinity Modulating Agents of Protein-Protein Interactions

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