title: New peptide inhibitors modulate the self-assembly of islet amyloid polypeptide residues 11-20 in vitro.
abstract: The structural transition and misfolding of human islet amyloid polypeptide may cause a common metabolic disease Type 2 diabetes mellitus. Seventeen peptides have been synthesized, possessing different lengths, compositions, and peptide conformation. In this study, the mechanism of these peptides on inhibiting the formation of hIAPP11-20amyloid fibrils was investigated using a conventional ThT fluorescence assay and microscale thermophoresis. The results showed that short peptides AT, SA, RF, KS, KT and KN, and cyclic peptides cyclic-KS, cyclic-KT and cyclic-KN displayed considerable inhibitory effect on hIAPP11-20fibril formation and a strong affinity for hIAPP11-20. The detailed investigation indicated that the phenylalanine residue and some special peptide composition significantly inhibit amyloid formation. The peptide conformation of the designed peptide inhibitors may also play an important role. Microscale thermophoresis quantified the binding affinities between hIAPP11-20and the peptides; and revealed that high affinity binding more likely leads to inhibiting fibril formation of hIAPP11-20and vice versa, which is in accordance with the results from the ThT assays. These findings suggest a feasible model of peptide inhibitor design for inhibiting amyloid formation. In addition, microscale thermophoresis was proven as a promising rapid method for preliminarily screening inhibitors of hIAPP11-20.
authors.affiliation: College of Chemistry and Molecular Engineering, Zhengzhou University, Kexue Road, Zhengzhou 450001, PR China.
authors.forename: Yexuan
authors.initials: Y
authors.lastname: Mao
authors.affiliation: College of Chemistry and Molecular Engineering, Zhengzhou University, Kexue Road, Zhengzhou 450001, PR China. Electronic address: yulanlan@zzu.edu.cn.
authors.forename: Lanlan
authors.initials: L
authors.lastname: Yu
authors.affiliation: College of Chemistry and Molecular Engineering, Zhengzhou University, Kexue Road, Zhengzhou 450001, PR China.
authors.forename: Ran
authors.initials: R
authors.lastname: Yang
authors.affiliation: National Engineering Laboratory for Wheat & Corn Further Processing, Henan University of Technology, Zhengzhou 450001, PR China.
authors.forename: Chuanguo
authors.initials: C
authors.lastname: Ma
authors.affiliation: College of Chemistry and Molecular Engineering, Zhengzhou University, Kexue Road, Zhengzhou 450001, PR China. Electronic address: qulingbo@zzu.edu.cn.
authors.forename: Lingbo
authors.initials: L
authors.lastname: Qu
authors.affiliation: Center for Intelligent Chemical Instrumentation, Department of Chemistry and Biochemistry, Clippinger Laboratories, OHIO University, Athens, OH 45701-2979 USA.
authors.forename: Peter de B
authors.initials: PB
authors.lastname: Harrington
mesh_terms: D000595:Amino Acid Sequence; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry*; D010446:Peptide Fragments / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D066329:Protein Aggregates / Q000187:drug effects*; D013816:Thermodynamics
chemical_list: D058228:Islet Amyloid Polypeptide; D010446:Peptide Fragments; D010455:Peptides; D066329:Protein Aggregates
keywords: Amyloid formation; Islet amyloid polypeptide; Microscale thermophoresis; Molecular interaction; Peptide inhibitors