The abnormal fibrillation of human islet amyloid polypeptide (hIAPP) is associated with development of type II diabetes mellitus (T2DM). (-)-Epigallocatechin gallate (EGCG) can bind amyloid proteins to inhibit the fibrillation of these proteins. However, the mechanic detail of EGCG inhibiting amyloid formation is still unclear at the molecular level. In the present work, we sought to investigate the effect of EGCG on amidated hIAPP (hIAPP-NH2 ) fibrillation and aggregation by using spectroscopic and microscopic techniques, and also sought to gain insights into the interaction of EGCG and hIAPP22-27 by using spectroscopic experiments and quantum chemical calculations. ThT fluorescence, real-time NMR, and TEM studies demonstrated that EGCG inhibits the formation of hIAPP-NH2 fibrils, while promoting the formation of hIAPP-NH2 amorphous aggregates. Phenylalanine intrinsic fluorescence and NMR studies of the EGCG/hIAPP22-27 complex revealed three important binding sites including the A ring of EGCG, residue Phe23, and residue Ile26. DFT calculations identified the dominant binding structures of EGCG/Phe23 and EGCG/Ile26 complexes, named structure I and structure II, respectively. Our study demonstrates the inhibitory mechanism of EGCG on fibrillation and aggregation of hIAPP-NH2 in which EGCG interacts with hIAPP-NH2 through hydrogen bonding and π-π interactions between the A ring and residue Phe23 as well as hydrophobic interactions between the A ring and residue Ile26, which can thus inhibit the interpeptide interaction between hIAPP-NH2 monomers and finally inhibit fibrillation of hIAPP-NH2 . This study agrees with and reinforces previous studies and offers an intuitive explanation at both the atomic and molecular levels. Our findings may provide an invaluable reference for the future development of new drugs in the management of diabetes.

Inhibitory Mechanism of Epigallocatechin Gallate on Fibrillation and Aggregation of Amidated Human Islet Amyloid Polypeptide

1013 Objectives We report here the synthesis of systematic derivatization of SB-13 by modifying its A-ring with various electron donating and electron withdrawing substituents, and its B-ring with varying size and polarity of N-substituents. Methods The stilbene derivatives (13-24) were successfully prepared by a Wadsworth-Emmons reaction. Also, to prepared the stilbene drivatives (25-44) were concerned about lipophilicity and polarity by sodium hydride, diethyl phosphates derivatives (1-12) and 4-(N-methyl-N-2-hydroxyethyl)benzaldehyde or 4-(N-methyl-N-2-cyanoethyl)benzaldehyde in THF at 80 °C for 5 h, giving with 20-48% yields. On the other hand, we could not prepared cyanoethyl group with 3’-or 4’-OCH3 and observed side products which were losing alkylsubstituted compounds (42-44). Results The synthesized stilbene derivatives were tested 32 compounds in synthetic Aβ40 agregates. Among them, four compounds showed over 6-fold increase at 30 μM concentrations of Aβ40 fibril. Compound 42, exhibited submicromolar dissociation constant (0.6 μM), which is superior than that of Thioflavin T (ThT: KD = 2.3 μM)—a conventional amyloid sensor. We further tested its applicability in the staining of amyloid plaques in AD-mouse brain sections. As compound 42 displays blue fluorescence, ThT (green) was used for complementary staining of amyloid plaques. Conclusions We prepared 32 new derivatives of the known β-amyloid plaques ligand, SB-13, and among them identified compound 42 with a sub-micromolar dissociation constant (0.6 μM) to Aβ40 aggregates. Compound 42 demonstrated its excellent capability of labeling Aβ aggregates in AD mouse brain with good colocalization with ThT. Based on their delicately high binding affinity to Aβ40 aggregates, these novel stilbene analogues may be good candidates for further modification for in vivo imaging probes by introducing PET or SPECT relevant isotopes

Synthesis and evaluation of stilbene derivatives as a potential imaging agent of amyloid plaques

Site-selective peptide/protein degradation through chemical cleavage methods is an important modification of biologically relevant macromolecules which complements enzymatic hydrolysis. In this review, recent progress in chemical, site-selective peptide bond cleavage is overviewed, with an emphasis on postulated mechanisms and their implications on reactivity, selectivity, and substrate scope.

Site-Selective Peptide/Protein Cleavage

The mechanism responsible for peptide bond hydrolysis by Co(III) and Cu(II) complexes with (oxa)cyclen ligands has been revisited by means of computational tools. We propose that the mechanism starts by substrate coordination and an outer-sphere attack on the amide C atom of a solvent water molecule assisted by the metal hydroxo moiety as a general base, which occurs through six-membered ring transition states. This new mechanism represents a more likely scenario than the previously proposed mechanisms that involved an inner-sphere nucleophilic attack through more strained four-membered rings transition states. The corresponding computed overall free-energy barrier of 25.2 kcal mol-1 for hydrolysis of the peptide bond in Phe-Ala by a cobalt(III) oxacyclen catalyst (1) is consistent with the experimental values obtained from rate constants. Also, we assessed the influence of the nature of the ligand throughout a systematic replacement of N by O atoms in the (oxa)cyclen ligand. Increasing the number of coordinating O atoms accelerates the reaction by increasing the Lewis acidity of the metal ion. On the other hand, the higher reactivity observed for the copper(II) oxacyclen catalyst with respect to the analogous Co(III) complex can be attributed to the larger Bronsted basicity of the copper(II) hydroxo ligand. Ultimately, the detailed understanding of the ligand and metal nature effects allowed us to identify the double role of the metal hydroxo complexes as Lewis acids and Bronsted bases and to rationalize the observed reactivity trends.

Peptide Hydrolysis by Metal (Oxa)cyclen Complexes: Revisiting the Mechanism and Assessing Ligand Effects.

Recent Trend in Catalysis for Degradation of Toxic Organophosphorus Compounds

Protective effects of cleavage agents on INS-1 cells against h-IAPP-induced apoptosis

A Study on the Decomposition of DFP using Cu(II)-Chitosan Complex

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Protective effects of cleavage agents on INS-1 cells against h-IAPP-induced apoptosis

A Study on the Decomposition of DFP using Cu(II)-Chitosan Complex