<i>In silico</i> peptide-directed ligand design complements experimental peptide-directed binding for protein–protein interaction modulator discovery

Howell, Lesley A.; Beekman, Andrew M.

doi:10.1039/d0cb00148a

Cited by 4 publications

(6 citation statements)

References 40 publications

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“…Fmoc-(S)-2-(4-pentenyl)Ala-OH (X) was introduced at the i, i+4 positions and following linear peptide synthesis and acetylation the staple was formed on resin using Grubbs 1 st gen. catalysed metathesis. 25 A fluorescently-tagged stapled peptide (16) Ac-…”

Section: Stapling Increases α-Helicity Binding Affinity and Stability...mentioning

confidence: 99%

“…The high-resolution structures of the telomerase H/ACA RNP suggest the dyskerin/dyskerin interaction is a head-to-tail interaction largely mediated by an α-helical section of 5′dyskerin (350MTTAVISTCDH360) 5,6 bound into a hydrophobic pocket in 3′-dyskerin from residues 46-76, dense in commonly observed early ageing mutations. 5,12 Following our work on inhibition of PPIs, [13][14][15][16] here we report the design and synthesis of peptidic inhibitors of this interaction.…”

Section: Introductionmentioning

confidence: 99%

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Peptide inhibitors of the dyskerin/dyskerin protein-protein interaction, a cancer target highlighted by Dyskeratosis Congenita mutations in ribonucleoproteins of telomerase.

van Wier,

Goddard,

Hyde

et al. 2024

Preprint

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A hallmark of cancer is the ability to replicate limitlessly making them immortal. In 80-90% of cancer cells this is due to the reactivation of telomerase, and elongation of telomeres. In patients with Dyskeratosis Congenita, a disease characterised by shortened telomeres, genetic mutations are transcribed to the dyskerin/dyskerin protein-protein interaction in the H/ACA ribonucleoprotein (RNP) module of telomerase. Based on the telomerase cryo-EM structure, we designed and synthesised linear, hydrocarbon and lactam stapled peptides, and developed in vitro fluorescence and homogenous time resolved fluorescence (HTRF) assays with recombinant MBP-dyskerin. Lead peptides were able to bind to dyskerin, prevent the dyskerin/dyskerin interactions. They inhibit cell growth in MCF-7 cells that demonstrate above average dyskerin expression but were unable to affect A549 cells with below average dyskerin expression. Results suggest inhibition of the protein interactions within the H/ACA RNP offer a new target for broad spectrum cancer treatment.

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Section: Stapling Increases α-Helicity Binding Affinity and Stability...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Peptide inhibitors of the dyskerin/dyskerin protein-protein interaction, a cancer target highlighted by Dyskeratosis Congenita mutations in ribonucleoproteins of telomerase.

van Wier,

Goddard,

Hyde

et al. 2024

Preprint

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“…To generate more drug-like agents, bifunctional systems, exploiting advantageous features of both peptides and small molecules, can be designed and evaluated with the support of in silico tools [47,48]. Indeed, once selected, a peptide with an established high affinity for a specific protein target and for which the 3D structure of the protein-peptide complex is available can be split into two fragments provided with a reduced (or not even appreciable) interaction affinity for the protein target.…”

Section: Brief Overview Of Peptide Therapeutic Potential: Major Drawb...mentioning

confidence: 99%

Virtual Screening of Peptide Libraries: The Search for Peptide-Based Therapeutics Using Computational Tools

Vincenzi,

Mercurio,

Leone

2024

IJMS

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Over the last few decades, we have witnessed growing interest from both academic and industrial laboratories in peptides as possible therapeutics. Bioactive peptides have a high potential to treat various diseases with specificity and biological safety. Compared to small molecules, peptides represent better candidates as inhibitors (or general modulators) of key protein–protein interactions. In fact, undruggable proteins containing large and smooth surfaces can be more easily targeted with the conformational plasticity of peptides. The discovery of bioactive peptides, working against disease-relevant protein targets, generally requires the high-throughput screening of large libraries, and in silico approaches are highly exploited for their low-cost incidence and efficiency. The present review reports on the potential challenges linked to the employment of peptides as therapeutics and describes computational approaches, mainly structure-based virtual screening (SBVS), to support the identification of novel peptides for therapeutic implementations. Cutting-edge SBVS strategies are reviewed along with examples of applications focused on diverse classes of bioactive peptides (i.e., anticancer, antimicrobial/antiviral peptides, peptides blocking amyloid fiber formation).

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“…This presentation will describe our advances on this technique and its application to new protein-protein interactions [ 17 , 18 ].…”

Section: Keynote Lecturesmentioning

confidence: 99%

30th Annual GP2A Medicinal Chemistry Conference

et al. 2023

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In silico peptide-directed ligand design complements experimental peptide-directed binding for protein–protein interaction modulator discovery

Abstract: Using the protein–protein interaction of Mcl-1/Noxa, two methods for efficient modulator discovery are directly compared.

Cited by 4 publications

References 40 publications

Peptide inhibitors of the dyskerin/dyskerin protein-protein interaction, a cancer target highlighted by Dyskeratosis Congenita mutations in ribonucleoproteins of telomerase.

Peptide inhibitors of the dyskerin/dyskerin protein-protein interaction, a cancer target highlighted by Dyskeratosis Congenita mutations in ribonucleoproteins of telomerase.

Virtual Screening of Peptide Libraries: The Search for Peptide-Based Therapeutics Using Computational Tools

30th Annual GP2A Medicinal Chemistry Conference

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