title: Probing the binding affinity of amyloids to reduce toxicity of oligomers in diabetes.
abstract: BACKGROUND
  Amyloids play a role in the degradation of β-cells in diabetes patients. In particular, short amyloid oligomers inject themselves into the membranes of these cells and create pores that disrupt the strictly controlled flow of ions through the membranes. This leads to cell death. Getting rid of the short oligomers either by a deconstruction process or by elongating them into longer fibrils will reduce this toxicity and allow the β-cells to live longer.
  
  
  RESULTS
  We develop a computational method to probe the binding affinity of amyloid structures and produce an amylin analog that binds to oligomers and extends their length. The binding and extension lower toxicity and β-cell death. The amylin analog is designed through a parsimonious selection of mutations and is to be administered with the pramlintide drug, but not to interact with it. The mutations (T9K L12K S28H T30K) produce a stable native structure, strong binding affinity to oligomers, and long fibrils. We present an extended mathematical model for the insulin-glucose relationship and demonstrate how affecting the concentration of oligomers with such analog is strictly coupled with insulin release and β-cell fitness.
  
  
  METHODS
  SEMBA, the tool to probe the binding affinity of amyloid proteins and generate the binding affinity scoring matrices and R-scores is available at: http://amyloid.cs.mcgill.ca
authors.affiliation: School of Computer Science and McGill Center for Bioinformatics, McGill University, Montreal, QC, Canada and.
authors.forename: Mohamed Raef
authors.initials: MR
authors.lastname: Smaoui
authors.affiliation: Institut de Physique Théorique, CEA-Saclay, 91191 Gif/Yvette Cedex, France.
authors.forename: Henri
authors.initials: H
authors.lastname: Orland
authors.affiliation: School of Computer Science and McGill Center for Bioinformatics, McGill University, Montreal, QC, Canada and.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Waldispühl
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D019295:Computational Biology / Q000379:methods; D003920:Diabetes Mellitus / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D058228:Islet Amyloid Polypeptide / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D009154:Mutation
chemical_list: D000682:Amyloid; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D058228:Islet Amyloid Polypeptide; C105254:pramlintide