Targeted inhibition of amyloidogenesis using a non-toxic, serum stable strategically designed cyclic peptide with therapeutic implications

Pariary, Ranit; Ghosh, Baijayanti; Bednarikova, Zuzana; Varnava, Kyriakos G.; Ratha, Bhisma N; Raha, Sreyan; Bhattacharyya, Dipita; Gažová, Zuzana; Sarojini, Vijayalekshmi; Mandal, A.; Bhunia, Anirban

doi:10.1016/j.bbapap.2020.140378

Cited by 12 publications

(6 citation statements)

References 60 publications

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“…Thus, it is critical to identify compounds that modulate the deleterious interactions of IDP oligomers with membranes. In this regard, several classes of compounds have been identified to date, including small molecules ( 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ), peptides/peptidomimetics ( 18 , 19 ), molecular chaperones ( 20 , 21 , 22 , 23 , 24 , 25 ), and antibodies ( 22 , 26 ). One notable ligand that has garnered significant attention in recent years is (-)-epigallocatechin-3-gallate (EGCG).…”

mentioning

confidence: 99%

Structural determinants of the interactions of catechins with Aβ oligomers and lipid membranes

Ahmed

Huang

Lifshitz

et al. 2022

Journal of Biological Chemistry

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The aberrant self-assembly of intrinsically disordered proteins (IDPs) into soluble oligomers and their interactions with biological membranes underlie the pathogenesis of numerous neurodegenerative diseases, including Alzheimer’s disease. Catechins have emerged as useful tools to reduce the toxicity of IDP oligomers by modulating their interactions with membranes. However, the structural determinants of catechin binding to IDP oligomers and membranes remain largely elusive. Here, we assemble a catechin library by combining several naturally occurring chemical modifications and, using a coupled NMR-statistical approach, we map at atomic resolution the interactions of such library with the Alzheimer’s-associated amyloid-beta (Aβ) oligomers and model membranes. Our results reveal multiple catechin affinity drivers and show that the combination of affinity-reducing covalent changes may lead to unexpected net gains in affinity. Interestingly, we find that the positive cooperativity is more prevalent for Aβ oligomers than membrane binding, and that the determinants underlying catechin recognition by membranes are markedly different from those dissected for Aβ oligomers. Notably, we find that the unanticipated positive cooperativity arises from the critical regulatory role of the gallate catechin moiety, which recruits previously disengaged substituents into the binding interface and leads to an overall greater compaction of the receptor-bound conformation. Overall, the previously elusive structural attributes mapped here provide an unprecedented foundation to establish structure-activity relationships of catechins.

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confidence: 99%

Structural determinants of the interactions of catechins with Aβ oligomers and lipid membranes

Ahmed

Huang

Lifshitz

et al. 2022

Journal of Biological Chemistry

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“…In order to do that, we performed an MTT assay of AV20 at two different time points of incubation, which was done without shaking. The MTT protocol is detailed in refs − . MTT results show that AV20 intermediates (20 μM) are toxic to the SH-SY5Y cell line when compared to control cells.…”

Section: Resultsmentioning

confidence: 99%

Solvent Relaxation NMR: A Tool for Real-Time Monitoring Water Dynamics in Protein Aggregation Landscape

Chakraborty

Kar

Sarkar

et al. 2021

ACS Chem. Neurosci.

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Solvent dynamics strongly induce the fibrillation of an amyloidogenic system. Probing the solvation mechanism is crucial as it enables us to predict different proteins’ functionalities, such as the aggregation propensity, structural flexibility, and toxicity. This work shows that a straightforward NMR method in conjunction with phenomenological models gives a global and qualitative picture of water dynamics at different concentrations and temperatures. Here, we study amyloid system Aβ40 and its fragment AV20 (A21-V40) and G37L (mutation at Gly37 → Leu of AV20), having different aggregation and toxic properties. The independent validation of this method is elucidated using all-atom classical MD simulation. These two state-of-the-art techniques are pivotal in linking the effect of solvent environment in the near hydration-shell to their aggregation nature. The time-dependent modulation in solvent dynamics probed with the NMR solvent relaxation method can be further adopted to gain insight into amyloidogenesis and link with their toxicity profiles.

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“…The uniform loss of signal intensities upon increasing concentrations of CBBG suggested upon a fast to intermediate exchange between the free and CBBGbound HI at the NMR time scale. 21,44 The intensity decay rate constants (Kd) of amide, aromatic and aliphatic regions (upon CBBG binding) were determined as 7.54 ± 2.56 µM, 5.26 ± 1.64 µM and 7.50 ± 1.56 µM, respectively ( Figure 3C, Table 1). The binding affinity determined from NMR was in close agreement with the ITC determined Kd values (12.5 µM) ( Table 1).…”

Section: The Insulin-cbbg Binding Interaction Is An Enthalpy-driven Pmentioning

confidence: 99%

“…It is reported that HI exists as a monomer in 20% acetic acid. 21,43,44 To identify the binding epitopes of monomeric HI by CBBG (HI:CBBG=1:1), we, again, recorded the NMR spectra of HI in 20% acetic acid-d 4 (pH=1.9) at room temperature ( Supplementary Figures S10 and S11). 1D and 2D NOESY NMR spectra of HI in the presence of equimolar CBBG revealed almost no significant chemical shift changes and line broadening effect, indicating that addition of CBBG did not induce any structural conformational changes within the residues of HI ( Supplementary Figures S10 and S11).…”

Section: Can Cbbg Interact With Monomeric Human Insulin?mentioning

confidence: 99%

Mechanistic Studies of the Stabilization of Insulin Helical Structure by Coomassie Brilliant Blue

Dolui¹,

Pariary

Saha³

et al. 2020

Preprint

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Human insulin (HI) is an essential protein hormone and its biological activity mostly depends on folded and active conformation in the monomeric state. The present investigation established that Coomassie Brilliant Blue G-250 (CBBG), a small multicyclic hydroxyl compound can reversibly bind to the hormonal protein dimer and maintained most of α-helical folds crucial for biological function of the enzyme. The solution-state 1D NMR and isothermal calorimetric analysis showed a sub-micromolar binding affinity of the molecule to HI. 2D NOESY NMR established that the HI dimer undergoes residue level local conformational change upon binding to CBBG. The chemical shift perturbation and the NOE parameters of active protons of amino acid residues throughout the polypeptides further suggested that CBBG upon binding the protein stabilize α-helixes of both the A and B subunits of the hormonal protein. The changes in Gibb’s free energy (∆G) of the binding was of ~−11.1 kcal/mol and suggested a thermodynamically favourable process. The changes in enthalpy (∆H) and entropy term (T∆S) were −57.2 kcal/mol and −46.1 kcal/mol, respectively. The negative changes in entropy and the NOE transfer effectiveness of several residues in the presence of CBBG molecules indicated that the binding was an enthalpy driven favourable equilibrium process. The NMR-based atomic resolution data and molecular docking studies confirmed that the CBBG binds to HI at the dimeric stage and prevents the availability of the crucial residue segments that partake directly in further oligomerization and subsequent fibrillation. Extended computational analysis based on chemical shift perturbation of protons of active residues further established receptor-ligand based pharmacophore model comprised of 5 hydrophobic and a hydrogen bond acceptor features that can anchor the residues at the A and B chains of HI and inhibit the partial unfolding and hydrophobic collapse to nucleate the fibrillation. Taken together, the results demonstrated that CBBG and their close analogues might be useful to develop a formulation that will maintain the active and functional form of the hormonal protein for a significantly longer time.TOC

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Targeted inhibition of amyloidogenesis using a non-toxic, serum stable strategically designed cyclic peptide with therapeutic implications

Cited by 12 publications

References 60 publications

Structural determinants of the interactions of catechins with Aβ oligomers and lipid membranes

Structural determinants of the interactions of catechins with Aβ oligomers and lipid membranes

Solvent Relaxation NMR: A Tool for Real-Time Monitoring Water Dynamics in Protein Aggregation Landscape

Mechanistic Studies of the Stabilization of Insulin Helical Structure by Coomassie Brilliant Blue

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