Unlocking novel therapies: cyclic peptide design for amyloidogenic targets through synergies of experiments, simulations, and machine learning

de Raffele, Daria; Ilie, Ioana M.

doi:10.1039/d3cc04630c

Cited by 5 publications

(3 citation statements)

References 193 publications

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“…In essence, this investigation sheds light on the impact of miniaturization on peptide binding to NFÀ YB/C, unraveling conformational flexibility and offering insights into peptide dynamics through MD simulations Our findings highlights the value simulations can add to the design of bioactive peptides. [22] And, they shed light on the critical role of flexibility in bound peptide ligands, a factor which has been reported to enhance the stability of peptide/protein complexes. [23]…”

Section: Discussionmentioning

confidence: 99%

Binding Dynamics of a Stapled Peptide Targeting the Transcription Factor NF−Y

Durukan,

Arbore,

Klintrot

et al. 2024

ChemBioChem

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Transcription factors (TFs) play a central role in gene regulation, and their malfunction can result in a plethora of severe diseases. TFs are therefore interesting therapeutic targets, but their involvement in protein‐protein interaction networks and the frequent lack of well‐defined binding pockets render them challenging targets for classical small molecules. As an alternative, peptide‐based scaffolds have proven useful, in particular with an α‐helical active conformation. Peptide‐based strategies often require extensive structural optimization efforts, which could benefit from a more detailed understanding of the dynamics in inhibitor/protein interactions. In this study, we investigate how truncated stapled α‐helical peptides interact with the transcription factor Nuclear Factor‐Y (NF‐Y). We identified a 13‐mer minimal binding core region, for which two crystal structures with an altered C‐terminal peptide conformation when bound to NF‐Y were obtained. Subsequent molecular dynamics simulations confirmed that the C‐terminal part of the stapled peptide is indeed relatively flexible while still showing defined interactions with NF‐Y. Our findings highlight the importance of flexibility in the bound state of peptides, which can contribute to overall binding affinity.

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Section: Discussionmentioning

confidence: 99%

Binding Dynamics of a Stapled Peptide Targeting the Transcription Factor NF−Y

Durukan,

Arbore,

Klintrot

et al. 2024

ChemBioChem

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“…Inflammatory processes play a multifaceted role in tumor development and progression [1][2][3][4][5][6][7]. While the immune system's inflammatory response is typically a defense mechanism against infections and tissue damage, chronic or persistent inflammation can contribute to the initiation, growth, and spread of certain types of tumors.…”

Section: Introductionmentioning

confidence: 99%

Nerve Growth Factor and the Role of Inflammation in Tumor Development

Ferraguti,

Terracina,

Tarani

et al. 2024

CIMB

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Nerve growth factor (NGF) plays a dual role both in inflammatory states and cancer, acting both as a pro-inflammatory and oncogenic factor and as an anti-inflammatory and pro-apoptotic mediator in a context-dependent way based on the signaling networks and its interaction with diverse cellular components within the microenvironment. This report aims to provide a summary and subsequent review of the literature on the role of NGF in regulating the inflammatory microenvironment and tumor cell growth, survival, and death. The role of NGF in inflammation and tumorigenesis as a component of the inflammatory system, its interaction with the various components of the respective microenvironments, its ability to cause epigenetic changes, and its role in the treatment of cancer have been highlighted in this paper.

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“…Recently, several strategies have been proposed involving the targeting of peptides to amyloidogenic proteins or specific amyloidogenic regions of proteins [ 34 , 35 ]. Studying the mechanisms of amyloid structure formation in antimicrobial peptides can provide a foundation for developing effective peptide-based antimicrobial agents [ 36 ].…”

Section: Introductionmentioning

confidence: 99%

Optimizing Antimicrobial Peptide Design: Integration of Cell-Penetrating Peptides, Amyloidogenic Fragments, and Amino Acid Residue Modifications

Kravchenko,

Domnin,

Grishin

et al. 2024

IJMS

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The escalating threat of multidrug-resistant pathogens necessitates innovative approaches to combat infectious diseases. In this study, we examined peptides R23FS*, V31KS*, and R44KS*, which were engineered to include an amyloidogenic fragment sourced from the S1 protein of S. aureus, along with one or two cell-penetrating peptide (CPP) components. We assessed the antimicrobial efficacy of these peptides in a liquid medium against various strains of both Gram-positive bacteria, including S. aureus (209P and 129B strains), MRSA (SA 180 and ATCC 43300 strains), and B. cereus (strain IP 5832), and Gram-negative bacteria such as P. aeruginosa (ATCC 28753 and 2943 strains) and E. coli (MG1655 and K12 strains). Peptides R23FS*, V31KS*, and R44KS* exhibited antimicrobial activity comparable to gentamicin and meropenem against all tested bacteria at concentrations ranging from 24 to 48 μM. The peptides showed a stronger antimicrobial effect against B. cereus. Notably, peptide R44KS* displayed high efficacy compared to peptides R23FS* and V31KS*, particularly evident at lower concentrations, resulting in significant inhibition of bacterial growth. Furthermore, modified peptides V31KS* and R44KS* demonstrated enhanced inhibitory effects on bacterial growth across different strains compared to their unmodified counterparts V31KS and R44KS. These results highlight the potential of integrating cell-penetrating peptides, amyloidogenic fragments, and amino acid residue modifications to advance the innovation in the field of antimicrobial peptides, thereby increasing their effectiveness against a broad spectrum of pathogens.

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Unlocking novel therapies: cyclic peptide design for amyloidogenic targets through synergies of experiments, simulations, and machine learning

Cited by 5 publications

References 193 publications

Binding Dynamics of a Stapled Peptide Targeting the Transcription Factor NF−Y

Binding Dynamics of a Stapled Peptide Targeting the Transcription Factor NF−Y

Nerve Growth Factor and the Role of Inflammation in Tumor Development

Optimizing Antimicrobial Peptide Design: Integration of Cell-Penetrating Peptides, Amyloidogenic Fragments, and Amino Acid Residue Modifications

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