Thermodynamic and kinetic approaches for drug discovery to target protein misfolding and aggregation

Vendruscolo, Michele

doi:10.1080/17460441.2023.2221024

Cited by 3 publications

(4 citation statements)

References 134 publications

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“…Such small molecule ligands fit within a cavity on the surface of a protein and therefore require their binding sites to be predominantly folded. By contrast, recognition of intrinsically disordered polypeptides using synthetic ligands is exceedingly rare. , Disordered regions of polypeptides are highly solvent exposed, and due to the lack of folding, their structural information is encoded simply into the sequence of amino acid residues. Therefore, targeting disordered regions of polypeptides has the potential to be predictive on the basis of the amino acid sequence.…”

Section: Introductionmentioning

confidence: 99%

Cucurbit[8]uril Binds Nonterminal Dipeptide Sites with High Affinity and Induces a Type II β-Turn

Suating,

Kimberly,

Ewe

et al. 2024

J. Am. Chem. Soc.

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In an effort to target polypeptides at nonterminal sites, we screened the binding of the synthetic receptor cucurbit[8]uril (Q8) to a small library of tetrapeptides, each containing a nonterminal dipeptide binding site. The resulting leads were characterized in detail using a combination of isothermal titration calorimetry, 1 H NMR spectroscopy, electrospray ionization time-of-flight mass spectrometry (ESI-TOF-MS), and X-ray crystallography. The equilibrium dissociation constant values determined for the binding of Q8 to nonterminal dipeptide sites Lys-Phe (KF) and Phe-Lys (FK) were 60 and 86 nm, respectively. These are to the best of our knowledge the highest affinities reported to date for any synthetic receptor targeting a nonterminal site on an unmodified peptide. A 0.79 Å resolution crystal structure was obtained for the complex of Q8 with the peptide Gly-Gly-Leu-Tyr-Gly-Gly-Gly (GGLYGGG) and reveals structural details of the pair-inclusion motif. The molecular basis for recognition is established to be the inclusion of the side chains of Leu and Tyr residues, as well as an extensive network of hydrogen bonds between the peptide backbone, the carbonyl oxygens of Q8, and proximal water molecules. In addition, the crystal structure reveals that Q8 induces a type II β-turn. The sequence-selectivity, high affinity, reversibility, and detailed structural characterization of this system should facilitate the development of applications involving ligand-induced polypeptide folding.

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Section: Introductionmentioning

confidence: 99%

Cucurbit[8]uril Binds Nonterminal Dipeptide Sites with High Affinity and Induces a Type II β-Turn

Suating,

Kimberly,

Ewe

et al. 2024

J. Am. Chem. Soc.

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“…In the broader context this work holds significance as detecting oligomeric distribution is a crucial step in drug discovery strategies, facilitating the systematic optimization of compounds potency during early drug discovery stages [15] …”

Section: Introductionmentioning

confidence: 99%

Characterizing the Oligomers Distribution along the Aggregation Pathway of Amyloid Aβ1‐40 by NMR

Pagano,

De Rosa,

Tomaselli

et al. 2024

Chemistry A European J

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This study delves into the early aggregation process of the Aβ1‐40 amyloid peptide, elucidating the associated oligomers distribution. Motivated by the acknowledged role of small oligomers in the neurotoxic damage linked to Alzheimer’s disease, we present an experimental protocol for preparing 26‐O‐acyl isoAβ1‐40, a modified Aβ1‐40 peptide facilitating rapid isomerization to the native amide form at neutral pH. This ensures seed‐free solutions, minimizing experimental variability. Additionally, we demonstrate the efficacy of coupling NMR diffusion ordered spectroscopy (DOSY) with the Inverse Laplace Transform (ILT) reconstruction method, for effective characterization of early aggregation processes. This innovative approach efficiently maps oligomers distributions across a wide spectrum of initial peptide concentrations offering unique insights into the evolution of oligomers relative populations. As a proof of concept, we demonstrate the efficacy of our approach assessing the impact of Epigallocathechin gallate, a known remodeling agent of amyloid fibrils, on the oligomeric distributions of aggregated Aß1‐40. The DOSY‐ILT proposed approach stands as a robust and discriminating asset, providing a powerful strategy for rapidly gaining insight into potential inhibitors’ impact on the aggregation process.

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“…The amyloid aggregation of these IDP proteins have been extensively studied in the last decades, and a very general mechanism has been proposed. 17 Amyloid aggregation is thought to involve a conformational change in the monomer that leads to a β-sheet rich structure and the formation of oligomers, which in turn can grow into protofibrils. Protofibrils can combine with other protofibrils and/or incorporate more monomers to grow into amyloid fibrils, as shown in Fig.…”

Section: Introductionmentioning

confidence: 99%

“…1 . 17 Alternatively, many recent studies point to the ability of these proteins to undergo liquid–liquid phase separation (LLPS), forming liquid droplets that can eventually lead to the formation of amyloid fibrils ( Fig. 1 ).…”

Section: Introductionmentioning

confidence: 99%

Copper binding and protein aggregation: a journey from the brain to the human lens

Posadas,

Sánchez-López,

Quintanar

2023

RSC Chem. Biol.

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Thermodynamic and kinetic approaches for drug discovery to target protein misfolding and aggregation

Cited by 3 publications

References 134 publications

Cucurbit[8]uril Binds Nonterminal Dipeptide Sites with High Affinity and Induces a Type II β-Turn

Cucurbit[8]uril Binds Nonterminal Dipeptide Sites with High Affinity and Induces a Type II β-Turn

Characterizing the Oligomers Distribution along the Aggregation Pathway of Amyloid Aβ1‐40 by NMR

Copper binding and protein aggregation: a journey from the brain to the human lens

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