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Peptide inhibitor of amyloidogenesis
Inhibitor1 was designed by Steven O. Smith and colleagues, Stony Brook University, to inhibit sheet-to-sheet packing in amyloid fibrils and disrupt fibril formation. Hydrophobic and hydrophilic amino acids alternate in the eight amino-acid Inh1 peptide (RGTFEGKF-NH2). This class of inhibitor would target amyloid diseases such as Alzheimer’s, Huntington’s and type II diabetes. Inh1 significantly reduces the toxicity induced by the Alzheimer’s Abeta42 peptide on cultured rat cortical neurons.
In Alzheimer peptides Abeta40 and Abeta42, Met 35 on the face of one unit-protofibril packs into the groove created by Gly33 (Abeta40) or Gly37 (Abeta42) on the face of an opposing unit-protofibril.
The alternating small and large amino acids on the hydrophobic face of Inh1 are designed to match the GxMxG face of the Abeta40/42 peptide.
Inhibitor of Amyloid Sheet-to-Sheet Packing Caps Heights Of Soluble Oligomers
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Images are taken in a 250 nm field with super sharp silicon tips.
Soluble oligomer structures were observed in parallel experiments 3 hrs following solubilization of aBeta42 peptide in the absence (top) and presence (bottom) of Inh1.
Inh1, present 10:1 to aBeta42, causes a marked change in the Z dimension and in number of oligomers. |
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Oligomer heights in the absence of Inh1 measure from 2 to 9 nm. In the presence of Inh1, measured heights form a narrow Gaussian distribution with a 2.8 nm average (SD 0.5 nm).
Error integral analysis indicates Inh1 has a highly significant effect of reducing stacking of aBeta42 oligomers with packing capped at 4 nm.
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