<i>In Silico</i>and<i>in Vitro</i>Study of Binding Affinity of Tripeptides to Amyloid β Fibrils: Implications for Alzheimer’s Disease

Man, Viet Hoang; Šipošová, Katarína; Bednarikova, Zuzana; Antošová, Andrea; Nguyen, Truc Trang; Gažová, Zuzana; Li, Mai Suan

doi:10.1021/acs.jpcb.5b00006

Cited by 34 publications

(32 citation statements)

References 89 publications

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“…Among the tripeptides, PWW exhibited the highest binding affinity toward amyloid fibers (35). Based on the hypothesis that amyloid fibers of different proteins often share similar structural properties, we were interested in testing the activity of KR7 with insulin, as the central region of the KR7 has overlapping PWW and WWP motifs.…”

Section: Peptide Designmentioning

confidence: 99%

Inhibition of Insulin Amyloid Fibrillation by a Novel Amphipathic Heptapeptide

Ratha¹,

Ghosh²,

Brender

et al. 2016

Journal of Biological Chemistry

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The aggregation of insulin into amyloid fibers has been a limiting factor in the development of fast acting insulin analogues, creating a demand for excipients that limit aggregation. Despite the potential demand, inhibitors specifically targeting insulin have been few in number. Here we report a non-toxic and serum stable-designed heptapeptide, KR7 (KPWWPRR-NH), that differs significantly from the primarily hydrophobic sequences that have been previously used to interfere with insulin amyloid fibrillation. Thioflavin T fluorescence assays, circular dichroism spectroscopy, and one-dimensional proton NMR experiments suggest KR7 primarily targets the fiber elongation step with little effect on the early oligomerization steps in the lag time period. From confocal fluorescence and atomic force microscopy experiments, the net result appears to be the arrest of aggregation in an early, non-fibrillar aggregation stage. This mechanism is noticeably different from previous peptide-based inhibitors, which have primarily shifted the lag time with little effect on later stages of aggregation. As insulin is an important model system for understanding protein aggregation, the new peptide may be an important tool for understanding peptide-based inhibition of amyloid formation.

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Section: Peptide Designmentioning

confidence: 99%

Inhibition of Insulin Amyloid Fibrillation by a Novel Amphipathic Heptapeptide

Ratha¹,

Ghosh²,

Brender

et al. 2016

Journal of Biological Chemistry

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“…To estimate the binding free energy by the MM-PBSA method, the molecular dynamics simulation was carried out with the AMBER-f99SB-ILDN force field [ 32 ] and water model TIP3P [ 33 ]. The rationale for our choice of AMBER-f99SB-ILDN is that this force field, as shown by previous work [ 9 , 34 – 36 ], provided reasonable results on binding affinity of small molecules to amyloid fibrils. The GAFF force field [ 37 ] was used for parameterization of ligands Hoechst 33342 and Hoechst 34580.…”

Section: Methodsmentioning

confidence: 95%

“…In the latter case Aβ oligomers or fibrils become the drug target. Following this strategy a lot of potential Aβ inhibitors have been identified including short peptides [ 9 ], nutraceuticals [ 10 – 13 ], polyamines [ 14 , 15 ], metal chelators [ 16 ], derivatives of vitamin K3 [ 17 ], RNA aptamers [ 18 ], osmolytes [ 19 ], and other compounds [ 15 , 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

Discovery of DNA dyes Hoechst 34580 and 33342 as good candidates for inhibiting amyloid beta formation: in silico and in vitro study

Thai

Tseng

et al. 2016

J Comput Aided Mol Des

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Combining Lipinski’s rule with the docking and steered molecular dynamics simulations and using the PubChem data base of about 1.4 million compounds, we have obtained DNA dyes Hoechst 34580 and Hoechst 33342 as top-leads for the Alzheimer’s disease. The binding properties of these ligands to amyloid beta (Aβ) fibril were thoroughly studied by in silico and in vitro experiments. Hoechst 34580 and Hoechst 33342 prefer to locate near hydrophobic regions with binding affinity mainly governed by the van der Waals interaction. By the Thioflavin T assay, it was found that the inhibition constant IC50 ≈ 0.86 and 0.68 μM for Hoechst 34580 and Hoechst 33342, respectively. This result qualitatively agrees with the binding free energy estimated using the molecular mechanic-Poisson Boltzmann surface area method and all-atom simulations with the AMBER-f99SB-ILDN force field and water model TIP3P. In addition, DNA dyes have the high capability to cross the blood brain barrier. Thus, both in silico and in vitro experiments have shown that Hoechst 34580 and 33342 are good candidates for treating the Alzheimer’s disease by inhibiting Aβ formation.Electronic supplementary materialThe online version of this article (doi:10.1007/s10822-016-9932-1) contains supplementary material, which is available to authorized users.

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“…The excitation and emission slits were adjusted to 9.0/9.0 nm, and the top probe vertical offset was 6 mm. 96−100…”

Section: Experimental Sectionmentioning

confidence: 99%

Nanomedical Relevance of the Intermolecular Interaction Dynamics—Examples from Lysozymes and Insulins

Zhang

Mohri

et al. 2019

ACS Omega

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Insulin and lysozyme share the common features of being prone to aggregate and having biomedical importance. Encapsulating lysozyme and insulin in micellar nanoparticles probably would prevent aggregation and facilitate oral drug delivery. Despite the vivid structural knowledge of lysozyme and insulin, the environment-dependent oligomerization (dimer, trimer, and multimer) and associated structural dynamics remain elusive. The knowledge of the intra- and intermolecular interaction profiles has cardinal importance for the design of encapsulation protocols. We have employed various biophysical methods such as NMR spectroscopy, X-ray crystallography, Thioflavin T fluorescence, and atomic force microscopy in conjugation with molecular modeling to improve the understanding of interaction dynamics during homo-oligomerization of lysozyme (human and hen egg) and insulin (porcine, human, and glargine). The results obtained depict the atomistic intra- and intermolecular interaction details of the homo-oligomerization and confirm the propensity to form fibrils. Taken together, the data accumulated and knowledge gained will further facilitate nanoparticle design and production with insulin or lysozyme-related protein encapsulation.

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In Silicoandin VitroStudy of Binding Affinity of Tripeptides to Amyloid β Fibrils: Implications for Alzheimer’s Disease

Cited by 34 publications

References 89 publications

Inhibition of Insulin Amyloid Fibrillation by a Novel Amphipathic Heptapeptide

Inhibition of Insulin Amyloid Fibrillation by a Novel Amphipathic Heptapeptide

Discovery of DNA dyes Hoechst 34580 and 33342 as good candidates for inhibiting amyloid beta formation: in silico and in vitro study

Nanomedical Relevance of the Intermolecular Interaction Dynamics—Examples from Lysozymes and Insulins

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