Analysis of the Ability of Pramlintide to Inhibit Amyloid Formation by XXXX Islet Amyloid Polypeptide Reveals a Balance between Optimum Recognition and Reduced Amyloidgenicity.

@entity1 @entity2175 @entity2532 @entity18670 @entity6 @entity35 @entity413
UNASSIGNED: The hormone @entity1 islet amyloid polypeptide ( @entity2532 or @entity2532 ) plays a role in @entity413 metabolism, but forms amyloid in the @entity2175 ( @entity2175 ) and is associated with b-cell death and dysfunction in the disease. Inhibitors of islet amyloid have therapeutic potential, however there are no clinically approved inhibitors and the mode of action of existing inhibitors is not well understood. @entity35 @entity18670 (rIAPP), differs from @entity2532 at six positions, does not form amyloid and is an inhibitor of amyloid formation by @entity2532 . Five of the six differences are located within residues 20-29, and three of them are Pro residues, which are well known disruptors of b-sheet structure. rIAPP is thus a natural example of a "b-breaker inhibitor"; a molecule which combines a recognition element with an entity that inhibits b-sheet formation. Pramlintide (PM) is a peptide drug approved for use as an adjunct to insulin therapy for treatment of @entity6 . PM was developed by introducing the three Pro substitutions found in rIAPP into @entity2532 . Thus, it more closely resembles the @entity1 peptide than does rIAPP. Here we examine and compare the ability of rIAPP, PM and a set of designed analogs of @entity2532 to inhibit amyloid formation by @entity2532 , in order to elucidate the factors which lead to effective peptide based inhibitors. Our results reveal, for this class of molecules, a balance between the reduced amyloidogenicity of the inhibitory sequence on the one hand and its ability to recognize @entity2532 on the other.
