title: Peptide Conjugates of Benzene Carboxylic Acids as Agonists and Antagonists of Amylin Aggregation.
abstract: Human islet amyloid polypeptide (hIAPP), also known as amylin, is a 37 residue peptide hormone that is stored and co-secreted with insulin. hIAPP plays a pivotal role in type 2 diabetes and is the major component of amyloid deposits found in the pancreas of patients afflicted with the disease. The self-assembly of hIAPP and the formation of amyloid is linked to the death of insulin producing β-cells. Recent findings suggest that soluble hIAPP oligomers are the cytotoxic species responsible for β-cell loss whereas amyloid fibrils themselves may indeed be innocuous. Potential avenues of therapeutic intervention include the development of compounds that prevent hIAPP self-assembly as well as those that reduce or eliminate lag time and rapidly accelerate the formation of amyloid fibrils. Both of these approaches minimize temporal exposure to soluble cytotoxic hIAPP oligomers. Toward this end our laboratory has pursued an electrostatic repulsion approach to the development of potential inhibitors and modulators of hIAPP self-assembly. Peptide conjugates were constructed in which benzene carboxylic acids of varying charge were employed as electrostatic disrupting elements and appended to the N-terminal of the hIAPP22-29(NFGAILSS) self-recognition sequence. The self-assembly kinetics of conjugates were characterized by turbidity measurements and the structure of aggregates probed by Raman and CD spectroscopy while the morphology was assessed using transmission electron microscopy. Several benzene carboxylic acid peptide conjugates failed to self-assemble and some were found to inhibit the aggregation of full-length amylin while others served to enhance the rate of amyloid formation and/or increase the yield of amyloid produced. Studies reveal that the geometric display of free carboxylates on the benzene ring of the conjugates plays an important role in the activity of conjugates. In addition, a number of free benzene carboxylic acids were found to modulate amylin self-assembly on their own. The results of these investigations confirm the viability of the electrostatic repulsion approach to the modulation of amyloid formation and may aid the design and development of potential therapeutic agents.
authors.affiliation: Department of Chemistry, York College and The Institute for Macromolecular Assemblies , Jamaica, New York 11451, United States.|Ph.D. Programs in Chemistry and Biochemistry, The Graduate Center of the City University of New York , New York, New York 10016, United States.
authors.forename: Adam A
authors.initials: AA
authors.lastname: Profit
authors.affiliation: Department of Chemistry, York College and The Institute for Macromolecular Assemblies , Jamaica, New York 11451, United States.|Ph.D. Programs in Chemistry and Biochemistry, The Graduate Center of the City University of New York , New York, New York 10016, United States.
authors.forename: Jayson
authors.initials: J
authors.lastname: Vedad
authors.affiliation: Department of Chemistry, York College and The Institute for Macromolecular Assemblies , Jamaica, New York 11451, United States.|Ph.D. Programs in Chemistry and Biochemistry, The Graduate Center of the City University of New York , New York, New York 10016, United States.
authors.forename: Ruel Z B
authors.initials: RZ
authors.lastname: Desamero
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000648:ultrastructure; D001554:Benzene / Q000737:chemistry / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D066329:Protein Aggregates / Q000187:drug effects*
chemical_list: D000682:Amyloid; D002264:Carboxylic Acids; D058228:Islet Amyloid Polypeptide; D010455:Peptides; D066329:Protein Aggregates; D001554:Benzene