Antifungal Activity of Gepinacin Scaffold Glycosylphosphatidylinositol Anchor Biosynthesis Inhibitors with Improved Metabolic Stability

Sean D Liston; Luke Whitesell; Catherine A McLellan; Ralph Mazitschek; Vidmantas Petraitis; Ruta Petraitiene; Povilas Kavaliauskas; Thomas J Walsh; Leah E Cowen

doi:10.1128/AAC.00899-20

Antifungal Activity of Gepinacin Scaffold Glycosylphosphatidylinositol Anchor Biosynthesis Inhibitors with Improved Metabolic Stability

Antimicrob Agents Chemother. 2020 Sep 21;64(10):e00899-20. doi: 10.1128/AAC.00899-20. Print 2020 Sep 21.

Authors

Affiliations

¹ Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
² Whitehead Institute, Cambridge, Massachusetts, USA.
³ Center for Systems Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁴ Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, New York, USA.
⁵ Department of Pediatrics, Weill Cornell Medicine and New York Presbyterian Hospital, New York, New York, USA.
⁶ Department of Microbiology & Immunology, Weill Cornell Medicine and New York Presbyterian Hospital, New York, New York, USA.
⁷ Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada leah.cowen@utoronto.ca.

Abstract

The glycosylphosphatidylinositol anchor biosynthesis inhibitor gepinacin demonstrates broad-spectrum antifungal activity and negligible mammalian toxicity in culture but is metabolically labile. The stability and bioactivity of 39 analogs were tested in vitro to identify LCUT-8, a stabilized lead with increased potency and promising single-dose pharmacokinetics. Unfortunately, no antifungal activity was seen at the maximum dosing achievable in a neutropenic rabbit model. Nevertheless, structure-activity relationships identified here suggest strategies to further improve compound potency, solubility, and stability.

Keywords: Gwt1; candidiasis; glycosylphosphatidylinositol; microsome metabolism; structure-activity relationship.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antifungal Agents* / pharmacology
Antifungal Agents* / therapeutic use
Glycosylphosphatidylinositols*
Rabbits
Structure-Activity Relationship

Substances

Antifungal Agents
Glycosylphosphatidylinositols