Design and study of peptide-based inhibitors of amylin cytotoxicity

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 4; pp. 1360 - 1362
• Main Authors: Muthusamy, Karen, Arvidsson, Per I., Govender, Patrick, Kruger, Hendrik G., Maguire, Glenn E.M., Govender, Thavendran
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15-02-2010; Elsevier
• Subjects: Amino Acid Sequence; Amylin; Amyloid - antagonists & inhibitors; Amyloid - genetics; Biological and medical sciences; Circular Dichroism; Cytotoxicity; Diabetes Mellitus, Type 2 - drug therapy; Drug Design; FARMACI; General and cellular metabolism. Vitamins; Humans; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - pharmacology; Islet Amyloid Polypeptide; Medical sciences; Molecular Sequence Data; N-Methylated; Peptides; Peptides - chemical synthesis; Peptides - genetics; Peptides - pharmacology; Pharmacology. Drug treatments; PHARMACY; Cytotoxicity; Peptides; N-Methylated; Amylin; Rat; Rodentia; Peptide hormone; In vitro; Biological activity; Hexapeptide; Vertebrata; Mammalia; Cell line; Peptide fragment; Circular dichroism spectrometry; Inhibitor; Peptide synthesis; Methylation; Pancreas
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2010.01.004

The incidence of type II diabetes is on the increase each year and the World Health Organisation (WHO) predicts there to be over 360 million diabetic patients worldwide by the year 2030. Deposits consisting mainly of a small protein, called islet amyloid polypeptide (amylin), which aggregates into oligo-/polymeric beta sheet structures is responsible for cytoxicity to the pancreatic β-cells, thus inhibition of this process has been explored as a potential prevention or treatment. N-Methylated and non N-methylated peptides spanning the length of amylin
1–37 were synthesised and evaluated for their inhibition of full length amylin mediated cytoxicity to RIN-5F cells. The non N-methylated peptides were very effective in inhibiting the cytotoxicity while the N-methylated peptides were not. Both the N-methylated and non N-methylated versions of the 29-34 region were equally effective.