Biochemistry Seminar: Andrew Miranker, "Membrane poration and cytotoxicity in diabetes: A small-molecule perspective"

ABSTRACT

Disordered proteins, such as those central to Alzheimer's, Parkinson's and Diabetes are particularly intractable to structure-targeted therapeutic design.  We recently demonstrated the capacity of a synthetic foldamer to stabilize structures formed by islet amyloid polypeptide (IAPP).  Oligoquinoline amides have a defined fold with a solvent-excluded core that is independent of its outwardly projected, derivatizable moieties. A tetraquinoline has been identified that stabilizes a non-amyloid membrane-associated conformation of IAPP. This charged, dianionic compound is readily soluble in aqueous buffer, yet crosses biological membranes without cellular assistance.  Inside the cell, the tetraquinoline docks specifically with intracellular IAPP and rescues insulin secreting b-cells from IAPP induced toxicity. Our recent efforts have focused on the mechanism of this tetraquinoline’s activity.  What is revealed is the small molecule is specific not only to human IAPP, but to a discrete sub-state within the ensemble of oligomers sampled by this protein. The nature of membrane poration is changed, but poration itself is not wholly eliminated.