title: C2'-OH of amphotericin B plays an important role in binding the primary sterol of human cells but not yeast cells.
abstract: Amphotericin B (AmB) is a clinically vital antimycotic but is limited by its severe toxicity. Binding ergosterol, independent of channel formation, is the primary mechanism by which AmB kills yeast, and binding cholesterol may primarily account for toxicity to human cells. The leading structural model predicts that the C2' hydroxyl group on the mycosamine appendage is critical for binding both sterols. To test this, the C2'-OH was synthetically deleted, and the sterol binding capacity of the resulting derivative, C2'deOAmB, was directly characterized via isothermal titration calorimetry. Surprisingly, C2'deOAmB binds ergosterol and, within the limits of detection of this experiment, does not bind cholesterol. Moreover, C2'deOAmB is nearly equipotent to AmB against yeast but, within the limits of detection of our assays, is nontoxic to human cells in vitro. Thus, the leading structural model for AmB/sterol binding interactions is incorrect, and C2'deOAmB is an exceptionally promising new antifungal agent.
authors.affiliation: Howard Hughes Medical Institute, Roger Adams Laboratory, Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Brandon C
authors.initials: BC
authors.lastname: Wilcock
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Endo
authors.forename: Brice E
authors.initials: BE
authors.lastname: Uno
authors.forename: Martin D
authors.initials: MD
authors.lastname: Burke
mesh_terms: D000666:Amphotericin B / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002176:Candida albicans / Q000737:chemistry / Q000166:cytology / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects*; D008968:Molecular Conformation; D012441:Saccharomyces cerevisiae / Q000737:chemistry / Q000166:cytology / Q000187:drug effects; D013261:Sterols / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; D013261:Sterols; D000666:Amphotericin B