Adam A Profit1, Jayson Vedad2, Mohamad Saleh2, Ruel Z B Desamero3. 1. York College, Institute for Macromolecular Assemblies and the Graduate Center of the City University of New York, Jamaica, NY 11451, United States. Electronic address: aprofit@york.cuny.edu. 2. York College, Institute for Macromolecular Assemblies and the Graduate Center of the City University of New York, Jamaica, NY 11451, United States. 3. York College, Institute for Macromolecular Assemblies and the Graduate Center of the City University of New York, Jamaica, NY 11451, United States. Electronic address: rdesamero@york.cuny.edu.
Abstract
A comprehensive investigation of peptides derived from the 22-29 region of human islet amyloid polypeptide (hIAPP) that contain phenylalanine analogs at position 23 with a variety of electron donating and withdrawing groups, along with heteroaromatic surrogates, has been employed to interrogate how π-electron distribution effects amyloid formation. Kinetic aggregation studies using turbidity measurements indicate that electron rich aromatic ring systems consistently abolish the amyloidogenic propensity of hIAPP(22-29). Electron poor systems modulate the rate of aggregation. Raman and Fourier transform infrared spectroscopy confirm the parallel β-sheet secondary structure of aggregates derived from peptides containing electron poor phenylalanine analogs and provide direct evidence of ring stacking. Transmission electron microscopy confirms the presence of amyloid fibrils. The effect of aryl substituent geometry on peptide self-assembly reveals that the electronic nature of substituents and not their steric profile is responsible for failure of the electron donating group peptides to aggregate. Non-aggregating hIAPP(22-29) peptides were found to inhibit the self-assembly of full-length hIAPP(1-37). The most potent inhibitory peptides contain phenylalanine with the p-amino and p-formamido functionalities. These novel peptides may serve as leads for the development of future aggregation inhibitors. A potential mechanism for inhibition of amylin self-assembly by electron rich (-29) peptides is proposed.
A comprehensive investigation of peptides derived from the 22-29 region of n class="Species">human islet amyloid polypeptide (hIAPP) that contain phenylalanine analogs at position 23 with a variety of electron donating and withdrawing groups, along with heteroaromatic surrogates, has been employed to interrogate how π-electron distribution effects amyloid formation. Kinetic aggregation studies using turbidity measurements indicate that electron rich aromatic ring systems consistently abolish the amyloidogenic propensity of hIAPP(22-29). Electron poor systems modulate the rate of aggregation. Raman and Fourier transform infrared spectroscopy confirm the parallel β-sheet secondary structure of aggregates derived from peptides containing electron poor phenylalanine analogs and provide direct evidence of ring stacking. Transmission electron microscopy confirms the presence of amyloid fibrils. The effect of aryl substituent geometry on peptide self-assembly reveals that the electronic nature of substituents and not their steric profile is responsible for failure of the electron donating group peptides to aggregate. Non-aggregating hIAPP(22-29) peptides were found to inhibit the self-assembly of full-length hIAPP(1-37). The most potent inhibitory peptides contain phenylalanine with the p-amino and p-formamido functionalities. These novel peptides may serve as leads for the development of future aggregation inhibitors. A potential mechanism for inhibition of amylin self-assembly by electron rich (-29) peptides is proposed.
Authors: I W Hamley; G D Brown; V Castelletto; G Cheng; M Venanzi; M Caruso; E Placidi; C Aleman; G Revilla-López; D Zanuy Journal: J Phys Chem B Date: 2010-08-19 Impact factor: 2.991
Authors: Jayson Vedad; Maciej E Domaradzki; Elmer-Rico E Mojica; Emmanuel J Chang; Adam A Profit; Ruel Z B Desamero Journal: J Raman Spectrosc Date: 2017-07-27 Impact factor: 3.133