Amphotericin B binds to amyloid fibrils and delays their formation: a therapeutic mechanism?
The membrane-active antifungal agent amphotericin B (AmB) is one of the few agents shown to slow the course of prion diseases in animals. Congo Red and other small molecules have been reported to directly inhibit amyloidogenesis in both prion and Alzheimer peptide model systems via specific binding. We propose that it is possible that AmB may act similarly to physically prevent conversion of the largely alpha-helical prion protein (PrP) to the pathological beta-sheet aggregate protease-resistant isoform (PrP(res)) in prion disease and by analogy prevent fibrillization in amyloid diseases. To assess whether AmB is capable of binding specifically to amyloid fibrils as does Congo Red, we have used the insulin fibril and Abeta 25-35 amyloid model fibril system. We find that AmB does bind strongly to both insulin (K(d) = 1.1 microM) and Abeta 25-35 amyloid (K(d) = 6.4 microM) fibrils but not to native insulin. Binding is characterized by a red-shifted AmB spectrum indicative of a more hydrophobic environment. Thus AmB seems to have a complementary face for amyloid fibrils but not the native protein. In addition, AmB interacts specifically with Congo Red, a known fibril-binding agent. In kinetic fibril formation studies, AmB was able to significantly kinetically delay the formation of Abeta 25-35 fibrils at pH 7.4 but not insulin fibrils at pH 2.
Hartsel
Scott C
SC
Department of Chemistry, University of Wisconsin-Eau Claire, 54702-4004, USA. hartsesc@uwec.edu
Weiland
Theodore R
TR
D000544:Alzheimer Disease / Q000188:drug therapy; D000666:Amphotericin B / Q000378:metabolism* / Q000627:therapeutic use; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D000935:Antifungal Agents / Q000378:metabolism; D003224:Congo Red / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007328:Insulin / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D017096:Prion Diseases / Q000188:drug therapy; D011485:Protein Binding; D013053:Spectrophotometry
D016229:Amyloid beta-Peptides; D000935:Antifungal Agents; D007328:Insulin; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); D003224:Congo Red; D000666:Amphotericin B