title: Disaggregation of Amylin Aggregate by Novel Conformationally Restricted Aminobenzoic Acid containing α/β and α/γ Hybrid Peptidomimetics.
abstract: Diabetes has emerged as a threat to the current world. More than ninety five per cent of all the diabetic population has type 2 diabetes mellitus (T2DM). Aggregates of Amylin hormone, which is co-secreted with insulin from the pancreatic β-cells, inhibit the activities of insulin and glucagon and cause T2DM. Importance of the conformationally restricted peptides for drug design against T2DM has been invigorated by recent FDA approval of Symlin, which is a large conformationally restricted peptide. However, Symlin still has some issues including solubility, oral bioavailability and cost of preparation. Herein, we introduced a novel strategy for conformationally restricted peptide design adopting a minimalistic approach for cost reduction. We have demonstrated efficient inhibition of amyloid formation of Amylin and its disruption by a novel class of conformationally restricted β-sheet breaker hybrid peptidomimetics (BSBHps). We have inserted β, γ and δ -aminobenzoic acid separately into an amyloidogenic peptide sequence, synthesized α/β, α/γ and α/δ hybrid peptidomimetics, respectively. Interestingly, we observed the aggregation inhibitory efficacy of α/β and α/γ BSBHps, but not of α/δ analogues. They also disrupt existing amyloids into non-toxic forms. Results may be useful for newer drug design against T2DM as well as other amyloidoses and understanding amyloidogenesis.
authors.affiliation: Laboratory of Peptide and Amyloid Research, Department of Chemistry, Indian Institute of Technology Guwahati, Assam- 781039, India.
authors.forename: Ashim
authors.initials: A
authors.lastname: Paul
authors.affiliation: Laboratory of Peptide and Amyloid Research, Department of Chemistry, Indian Institute of Technology Guwahati, Assam- 781039, India.
authors.forename: Sourav
authors.initials: S
authors.lastname: Kalita
authors.affiliation: Laboratory of Peptide and Amyloid Research, Department of Chemistry, Indian Institute of Technology Guwahati, Assam- 781039, India.
authors.forename: Sujan
authors.initials: S
authors.lastname: Kalita
authors.affiliation: Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam-781039, India.|Leeds Institute of Cardiovascular and Metabolic Medicine, LIGHT Laboratories, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Piruthivi
authors.initials: P
authors.lastname: Sukumar
authors.affiliation: Laboratory of Peptide and Amyloid Research, Department of Chemistry, Indian Institute of Technology Guwahati, Assam- 781039, India.
authors.forename: Bhubaneswar
authors.initials: B
authors.lastname: Mandal
mesh_terms: D062365:Aminobenzoates / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism*; D058228:Islet Amyloid Polypeptide / Q000378:metabolism*; D057786:Peptidomimetics / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism*; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological
chemical_list: D062365:Aminobenzoates; D007004:Hypoglycemic Agents; D058228:Islet Amyloid Polypeptide; D057786:Peptidomimetics; D066329:Protein Aggregates