Design of Peptide-based Inhibitors of Human Islet Amyloid Polypeptide Fibrillogenesis

Scrocchi, Louise A.; Chen, Yan; Waschuk, Stefko; Wang, Feng; Cheung, Sindy; Darabie, Audrey A.; McLaurin, JoAnne; Fraser, Paul E.

doi:10.1016/s0022-2836(02)00164-x

Cited by 140 publications

(173 citation statements)

References 37 publications

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“…Our work is inspired by previous studies that demonstrated the ability of amyloidogenic peptide fragments to inhibit fibrillization of polypeptides containing the cognate peptide sequences (25)(26)(27)(28)(29)(30)(31). A common concern when using amyloidogenic peptides as aggregation inhibitors is their poor solubility.…”

Section: Discussionmentioning

confidence: 99%

Rational design of potent domain antibody inhibitors of amyloid fibril assembly

Ladiwala

Bhattacharya

Perchiacca

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

100

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Fig. 7. IAPP and α-Synuclein gammabodies potently inhibit amyloid formation in a sequence-specific manner. IAPP (32 μM) and α-Synuclein (residues 1-115, 50 μM) were incubated in the absence (control) and presence of gammabodies (1:10 gammabody:monomer molar ratio), and fibrillization was monitored via (A) immunoblotting and (B) AFM. In B, IAPP and α-Synuclein fibrillization was also monitored in the presence of sequence-specific (R10/99, IAPP residues 7-17; 5C2, α-Synuclein residues 61-95) and conformation-specific (A11, prefibrillar oligomers; OC, fibrillar conformers) antibodies (1:10 antibody:monomer molar ratio). In B, the AFM images are 3 × 3 μm, and the blank images are samples with heights <1 nm. The heights of the IAPP and α-Synuclein aggregates are 21 ± 3 and 25 ± 4 nm, respectively.

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Section: Discussionmentioning

confidence: 99%

Rational design of potent domain antibody inhibitors of amyloid fibril assembly

Ladiwala

Bhattacharya

Perchiacca

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

100

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“…Socalled beta-sheet breaker peptides which bind specifically to amyloidogenic monomers to prevent refolding have been designed [128,129]. These small compounds provide the best option for treatment of islet amyloidosis at present.…”

Section: Resultsmentioning

confidence: 99%

Islet amyloid: a complication of islet dysfunction or an aetiological factor in Type 2 diabetes?

2004

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The role of islet amyloidosis in the onset and progression of Type 2 diabetes remains obscure. Islet amyloid polypeptide is a 37 amino-acid, beta-cell peptide which is co-stored and co-released with insulin. Human islet amyloid polypeptide refolds to a β-conformation and oligomerises to form insoluble fibrils; proline substitutions in rodent islet amyloid polypeptide prevent this molecular transition. Pro-islet amyloid polypeptide (67 amino acids in man) is processed in secretory granules. Refolding of islet amyloid polypeptide may be prevented by intragranular heterodimer formation with insulin (but not proinsulin). Diabetes-associated abnormal proinsulin processing could contribute to de-stabilisation of granular islet amyloid polypeptide. Increased pro-islet amyloid polypeptide secretion as a consequence of islet dysfunction could promote fibrillogenesis; the propeptide forms fibrils and binds to basement membrane glycosamino-glycans. Islet amyloid polypeptide gene polymorphisms are not universally associated with Type 2 diabetes. Transgenic mice expressing human islet amyloid polypeptide gene have increased islet amyloid polypeptide concentrations but develop islet amyloid only against a background of obesity and/or high fat diet. In transgenic mice, obese monkeys and cats, initially small perivascular deposits progressively increase to occupy 80% islet mass; the severity of amyloidosis in animal models is related to the onset of hyperglycaemia, suggesting that islet amyloid and the associated destruction of islet cells cause diabetes. In human diabetes, islet amyloid can affect less than 1% or up to 80% of islets indicating that islet amyloidosis largely results from diabetes-related pathologies and is not an aetiological factor for hyperglycaemia. However, the associated progressive betacell destruction leads to severe islet dysfunction and insulin requirement. [Diabetologia (2004) 47:157-169]

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“…Scrocchi et al have reported that peptides representing residues 20-25 and 24-29 can act as inhibitors of fibril formation by full-length amylin, while a peptide representing residues 22-27 accelerates fibril formation (91). Similarly, Porat et al have shown that a peptide representing residues 22-28, with a F23Y substitution, inhibits fibril formation (83).…”

Section: Comparison With Earlier Studies Of Amylin Fibrilsmentioning

confidence: 99%

“…In light of the models in Figure 11, the critical difference between the two sequences seems to be the proline substitutions at Ser28 and Ser29, which would disrupt the C-terminal β-sheets. Biophysical studies by Abedini and Raleigh (88) have shown that amyloid formation by human amylin can also be inhibited by simultaneous proline substitutions at residues 17, 19, and 30, without changing the sequence in residues 20-29, a segment that has been suggested (89) and subsequently discussed (56,83,90,91) as the "core" for amylin fibril formation. According to our data, residues 17 and 30 are in the C-terminal and N-terminal β-strands in amylin fibrils, respectively.…”

Section: Comparison With Earlier Studies Of Amylin Fibrilsmentioning

confidence: 99%

Peptide Conformation and Supramolecular Organization in Amylin Fibrils: Constraints from Solid-State NMR

et al. 2007

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The 37-residue amylin peptide, also known as islet amyloid polypeptide, forms fibrils that are the main peptide or protein component of amyloid that develops in the pancreas of type 2 diabetes patients. Amylin also readily forms amyloid fibrils in vitro that are highly polymorphic under typical experimental conditions. We describe a protocol for the preparation of synthetic amylin fibrils that exhibit a single predominant morphology, which we call a striated ribbon, in electron microscope and atomic force microscope images. Solid state nuclear magnetic resonance (NMR) measurements on a series of isotopically labeled samples indicate a single molecular structure within the striated ribbons. We use scanning transmission electron microscopy and several types of one-dimensional and two-dimensional solid state NMR techniques to obtain constraints on the peptide conformation and supramolecular structure in these amylin fibrils, and derive molecular structural models that are consistent with the experimental data. The basic structural unit in amylin striated ribbons, which we call the protofilament, contains four-layers of parallel β-sheets, formed by two symmetric layers of amylin molecules. The molecular structure of amylin protofilaments in striated ribbons closely resembles the protofilament in amyloid fibrils with similar morphology formed by the 40-residue β-amyloid peptide that is associated with Alzheimer's disease. Keywordsislet amyloid polypeptide; type 2 diabetes; amyloid fibril structure; electron microscopy; atomic force microscopy Amylin, also called islet amyloid polypeptide or IAPP, is a 37-residue peptide that is cosecreted with insulin by the β-cells of pancreas. The normal biological effects of amylin secretion include inhibition of glucagon secretion and reduction of the rate of gastric emptying, effects that contribute to the maintenance of postprandial glucose homeostasis (1). Amylin is the major peptide or protein component of the islet amyloid found in the pancreas of approximately 90% of type 2 (or non-insulin-dependent) diabetes patients (2,3). Fibrillar amylin has been shown * Corresponding author: Dr. Robert Tycko, National Institutes of Health, Building 5, Room 112, Bethesda, MD 20892-0520. phone 301-402-8272. fax 301-496-0825. e-mail robertty@mail.nih.gov.Supporting Information Available HPLC chromatograms from the purification of both reduced and oxidized amylin by reverse-phase chromatography ( Figure S1); FPLC chromatograms from the purification of both human and rodent amylin by size-exclusion chromatography ( Figure S2); 1D 13 C spectra of amylin fibrils with various isotopic labeling patterns, in lyophilized and rehydrated conditions ( Figures S3-S5); Table of 13 C NMR chemical shifts in amylin fibrils, TALOS predictions of backbone torsion angles based on these shifts, and torsion angles determined from 15 N fpRFDR-CT measurements (Table S1). This material is freely available on the World Wide Web at http://www.acs.org. to be toxic to cultured β-cells (4), and has been propo...

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Design of Peptide-based Inhibitors of Human Islet Amyloid Polypeptide Fibrillogenesis

Cited by 140 publications

References 37 publications

Rational design of potent domain antibody inhibitors of amyloid fibril assembly

Rational design of potent domain antibody inhibitors of amyloid fibril assembly

Islet amyloid: a complication of islet dysfunction or an aetiological factor in Type 2 diabetes?

Peptide Conformation and Supramolecular Organization in Amylin Fibrils: Constraints from Solid-State NMR

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