Enhancing the binding of the β-sheet breaker peptide LPFFD to the amyloid-β fibrils by aromatic modifications: A molecular dynamics simulation study

Kanchi, Pavan Krishna; Dasmahapatra, Ashok Kumar

doi:10.1016/j.compbiolchem.2021.107471

Cited by 13 publications

(8 citation statements)

References 99 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%

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%

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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“…In addition, the phenomenon of aggregation can be found in T1CEh-KKPWW2 at a high concentration, achieving hydrogel. The aromatic stacking which may cause complicated π−π interactions played a role in the self-assembly in many amyloid-related proteins [ 52 , 53 ]. At the same time, the increase of hydrophobicity which resulted from the accumulation of a hydrophobic amino acid contributed to the aggregation between peptide molecules [ 54 , 55 ].…”

Section: Discussionmentioning

confidence: 99%

In Vitro & In Vivo Studies on Identifying and Designing Temporin-1CEh from the Skin Secretion of Rana chensinensis as the Optimised Antibacterial Prototype Drug

Zhou

et al. 2022

Pharmaceutics

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Amphibian skin secretion is an ideal source of antimicrobial peptides that are difficult to induce drug resistance to due to their membrane-targeting mechanism as a new treatment scheme. In this study, a natural antimicrobial peptide Temporin-1CEh was identified by molecular cloning and mass spectrometry from the skin secretions of the Chinese forest frog (Rana chensinensis). Through the study of the structure and biological activity, it was found that Temporin-1CEh was a helical peptide from the Temporin family, and possessed good anti-Gram-positive bacteria activity through the mechanism of membrane destruction. Seven analogues were further designed to obtain broad-spectrum antimicrobial activity and higher stability in different physiological conditions. The results showed that T1CEh-KKPWW showed potent antibacterial activity with significantly increasing the activity against Gram-negative bacteria in vitro and in vivo with low haemolysis. In addition, T1CEh-KKPWW2 showed high sensitivity to the pH, serum or salts conditions, which applied a branched structure to allow the active units of the peptide to accumulate. Even though the haemolytic activity was increased, the stable antibacterial activity made this novel analogue meet the conditions to become a potential candidate in future antimicrobial and antibiofilm applications.

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“…Also, in preformed fibril states, His6, His13 & His14 molecules play a significant role in mediating zinc-induced oligomerization of fibrils. C1 peptide interacted with N-terminus Phe3, His14, Asp7, and Val12 and reported that it significantly destabilizes the amyloid-beta aggregates [46]. From the output, P6 and P12 were further tested for stability and interaction by MD Simulations which provide biological medium computationally and are used as a validation tool in CADD.…”

Section: Molecular Docking Analysismentioning

confidence: 99%

In silico identification of novel peptides as potential modulators of Aβ42 Amyloidogenesis

Kundal

Paramasivam

Mitra

et al. 2022

Preprint

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Alzheimer’s Disease is a neurodegenerative disease for which no cure is available at present. The presence of amyloid plaques in the extracellular space of neural cells is the key feature of this fatal disease. Amyloid-Beta (Aβ) is a 40-42 amino acid peptide and the main component of amyloid plaques. This peptide is produced by the proteolysis of Amyloid Precursor Protein by presenilin. Deposition of 42 residual Aβ peptides forms fibrils structure, leading to disruption of neuron synaptic transmission, inducing neural cell toxicity, ultimately leading to neuron death. To modulate the amyloidosis of Aβ peptides, various novel peptides have been investigated via molecular docking and molecular dynamic simulation studies. The sequence-based peptides were designed and investigated for their interaction with Aβ42 monomer and fibril using the molecular docking method, and their influence on the structural stability of target proteins was studied using molecular simulations. According to the docking results, amongst all the synthetic peptides, the peptide YRIGY (P6) has the highest binding affinity with Aβ42 fibril, and the peptide DKAPFF (P12) shows better binding with Aβ42 monomer. Moreover, simulation results also suggest that the higher the binding affinity, the better the inhibitory action. From these findings, it is suggested that both the peptides can modulate the amyloidogenesis, but peptide (P6) has better potential for the disaggregation of the fibrils, whereas peptide P12 stabilizes the native structure of the Aβ42 monomer more effectively and hence can serve as a potential amyloid inhibitor. Thus, these peptides can be explored as therapeutic agents against Alzheimer’s Disease.

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Enhancing the binding of the β-sheet breaker peptide LPFFD to the amyloid-β fibrils by aromatic modifications: A molecular dynamics simulation study

Cited by 13 publications

References 99 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

In Vitro & In Vivo Studies on Identifying and Designing Temporin-1CEh from the Skin Secretion of Rana chensinensis as the Optimised Antibacterial Prototype Drug

In silico identification of novel peptides as potential modulators of Aβ42 Amyloidogenesis

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