Destabilization of the Alzheimer’s amyloid-β peptide by a proline-rich β-sheet breaker peptide: a molecular dynamics simulation study

Kanchi, Pavan Krishna; Dasmahapatra, Ashok Kumar

doi:10.1007/s00894-021-04968-x

Cited by 13 publications

(9 citation statements)

References 93 publications

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“…We decided on proline as our preferred choice of aggregation suppressor based on the presumption that if a mutation can destabilize a protein in its monomeric form, it might also have the potential to destabilize the fibrillar form of the protein in the multimeric form. The usage of proline, using its natural and slightly modified derivatives − with varying concentrations, , as potential aggregation suppressors have been reported earlier by various reproach groups, though sporadically, indicating its efficiency as aggregation suppressor for Aβ ,,,,− along with few other proteins. ,,,, …”

Section: Discussionmentioning

confidence: 79%

“…Apart from the rank ordering of the kinetically controlled aggregation propensity, the above exercise additionally proves the effectivity of the proline residue as a great deterrent of aggregation as each of the segments shows lower aggregation propensity in the presence of proline substituents. The order of impact of proline follows the aggregation propensity trend, i.e., proline suppresses the aggregation propensity at the best limit for L17-D23, ,,,,− and the impact gradually decreases to G9-H14 and finally to V24-K28 . Rather than choosing a specific residue for each segment to be substituted by proline, we preferred to choose a proline-only sequence of equal length in each case to test the aggregation suppressibility for our initial guesswork.…”

Section: Discussionmentioning

confidence: 99%

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Scan-Find-Scan-Model: Discrete Site-Targeted Suppressor Design Strategy for Amyloid-β

Bhagavatula¹,

Sarkar

Santra

et al. 2022

ACS Chem. Neurosci.

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Alzheimer’s disease is undoubtedly the most well-studied neurodegenerative disease. Consequently, the amyloid-β (Aβ) protein ranks at the top in terms of getting attention from the scientific community for structural property-based characterization. Even after decades of extensive research, there is existing volatility in terms of understanding and hence the effective tackling procedures against the disease that arises due to the lack of knowledge of both specific target- and site-specific drugs. Here, we develop a multidimensional approach based on the characterization of the common static-dynamic-thermodynamic trait of the monomeric protein, which efficiently identifies a small target sequence that contains an inherent tendency to misfold and consequently aggregate. The robustness of the identification of the target sequence comes with an abundance of a priori knowledge about the length and sequence of the target and hence guides toward effective designing of the target-specific drug with a very low probability of bottleneck and failure. Based on the target sequence information, we further identified a specific mutant that showed the maximum potential to act as a destabilizer of the monomeric protein as well as enormous success as an aggregation suppressor. We eventually tested the drug efficacy by estimating the extent of modulation of binding affinity existing within the fibrillar form of the Aβ protein due to a single-point mutation and hence provided a proof of concept of the entire protocol.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Scan-Find-Scan-Model: Discrete Site-Targeted Suppressor Design Strategy for Amyloid-β

Bhagavatula¹,

Sarkar

Santra

et al. 2022

ACS Chem. Neurosci.

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“…To ascertain the dominant role of hydrophobic interactions in the inhibition process, we further employed the Nile red (NR) fluorescence assay; a reliable technique to probe the formation of molten globular states and the exposure of hydrophobic regions within proteins. 30 NR serves as a robust hydrophobic fluorescence marker, exhibiting a strong intensity and a notable blueshift in its maximum emission when binding to protein hydrophobic residues. Under normal circumstances, the hydrophobic amino acid residues in proteins are securely buried within the core of their folded structures, shielded from the encompassing solvent.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…23,24 Variants of 16KLVFF20 show efficacy in breaking β-sheets in amyloid beta peptides, making them potential peptide-based drugs for AD. 25,26 Proline, 27 proline functionalized gold nanoparticles, 28 and side-chain proline-based polymers 29 are already reported as potent inhibitors for the protein fibrillation process. It is expected that the limitations of small-molecule inhibitors, such as bioavailability and the surface area of interaction, can be overcome by incorporating proline (β-sheet breaker) 30 in the side-chain of the polymer and serving as peptide mimetics.…”

Section: ■ Introductionmentioning

confidence: 99%

Amyloid β-Peptide Segment Conjugated Side-Chain Proline-Based Polymers as Potent Inhibitors in Lysozyme Amyloidosis

Nayak,

Ghosh,

Barman

et al. 2024

Bioconjugate Chem.

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Developing effective amyloidosis inhibitors poses a significant challenge due to the dynamic nature of the protein structures, the complex interplay of interfaces in protein–protein interactions, and the irreversible nature of amyloid assembly. The interactions of amyloidogenic polypeptides with other peptides play a pivotal role in modulating amyloidosis and fibril formation. This study presents a novel approach for designing and synthesizing amyloid interaction surfaces using segments derived from the amyloid-promoting sequence of amyloid β-peptide [VF(Aβ(18–19)/FF(Aβ(19–20)/LVF(Aβ(17–19)/LVFF(Aβ(17–20)], where VF, FF, LVF and LVFF stands for valine phenylalanine dipeptide, phenylalanine phenylalanine dipeptide, leucine valine phenylalanine tripeptide and leucine valine phenylalanine phenylalanine tetrapeptide, respectively. These segments are conjugated with side-chain proline-based methacrylate polymers serving as potent lysozyme amyloidosis inhibitors and demonstrating reduced cytotoxicity of amyloid aggregations. Di-, tri-, and tetra-peptide conjugated chain transfer agents (CTAs) were synthesized and used for the reversible addition–fragmentation chain transfer polymerization of tert-butoxycarbonyl (Boc)-proline methacryloyloxyethyl ester (Boc-Pro-HEMA). Deprotection of Boc-groups from the side-chain proline pendants resulted in water-soluble polymers with defined peptide chain ends as peptide–polymer bioconjugates. Among them, the LVFF-conjugated polymer acted as a potent inhibitor with significantly suppressed lysozyme amyloidosis, a finding supported by comprehensive spectroscopic, microscopic, and computational analyses. These results unveil the synergistic effect between the segment-derived amyloid β-peptide and side-chain proline-based polymers, offering new prospects for targeting lysozyme amyloidosis.

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“…We defined a segment, KLVFF, Aβ (16–20), as the minimum sequence for aggregation and demonstrated that this segment could be targeted for drug development. The simple addition of a proline-rich peptide to break β-sheets increased affinity . A larger fragment Aβ (13–26) “clamped” to stabilize the structure was found to protect against neurotoxicity in hippocampal slices …”

Section: Introductionmentioning

confidence: 99%

Small Molecule Decoys of Aggregation for Elimination of Aβ-Peptide Toxicity

Oasa

Kouznetsova

Tiiman

et al. 2023

ACS Chem. Neurosci.

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Several lines of evidence suggest that a characteristic of the neuropathology of Alzheimer’s disease (AD) is the aggregation of the amyloid beta peptides (Aβ), fragments of the human amyloid precursor protein (hAPP). The dominating species are the Aβ40 and Aβ42 fragments with 40 and 42 amino acids, respectively. Aβ initially forms soluble oligomers that continue to expand to protofibrils, suggestively the neurotoxic intermediates, and thereafter turn into insoluble fibrils that are markers of the disease. Using the powerful tool of pharmacophore simulation, we selected small molecules not known to possess central nervous system (CNS) activity but that might interact with Aβ aggregation, from the NCI Chemotherapeutic Agents Repository, Bethesda, MD. We assessed the activity of these compounds on Aβ aggregation using the thioflavin T fluorescence correlation spectroscopy (ThT-FCS) assay. Förster resonance energy transfer-based fluorescence correlation spectroscopy (FRET-FCS) was used to characterize the dose-dependent activity of selected compounds at an early stage of Aβ aggregation. Transmission electron microscopy (TEM) confirmed that the interfering substances block fibril formation and identified the macrostructures of Aβ aggregates formed in their presence. We first found three compounds generating protofibrils with branching and budding never observed in the control. One compound generated a two-dimensional sheet structure and another generated a double-stranded filament. Importantly, these compounds generating protofibrils with altered macrostructure protected against Aβ-induced toxicity in a cell model while showing no toxicity in a model of cognition in normal mice. The data suggest that the active compounds act as decoys turning the aggregation into nontoxic trajectories and pointing toward novel approaches to therapy.

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Destabilization of the Alzheimer’s amyloid-β peptide by a proline-rich β-sheet breaker peptide: a molecular dynamics simulation study

Cited by 13 publications

References 93 publications

Scan-Find-Scan-Model: Discrete Site-Targeted Suppressor Design Strategy for Amyloid-β

Scan-Find-Scan-Model: Discrete Site-Targeted Suppressor Design Strategy for Amyloid-β

Amyloid β-Peptide Segment Conjugated Side-Chain Proline-Based Polymers as Potent Inhibitors in Lysozyme Amyloidosis

Small Molecule Decoys of Aggregation for Elimination of Aβ-Peptide Toxicity

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