The goal is to gain an understanding at the molecular level of the mechanism of action of the antifungal properties associated with the polyene macrolide antibiotics. The design and synthesis of unnatural compounds will be pursued with the objective of realizing antifungal agents of improved therapeutic efficacy. This study is simultaneously pursuing three interrelated avenues of investigation: a. the development of a general synthetic approach the polyene macrolide class of antibiotics, b. the synthesis of simplified polyene macrolide analogs, and c. physical studies aimed at understanding the structural details of the critical polyene-sterol interactions required for fungicidal activity. Within the context of the synthetic studies, general problems in acyclic asymmetric synthesis are being addressed, principally through diastereoselective elaboration of L-aspartic acid. As synthetic methodology is developed, access to increasingly diverse analogs to the natural polyene macrolides becomes available to test the structural features of these compounds that lead to selective binding with certain sterols. These studies are further supported by spectroscopic (i.e., NMR) efforts to directly observe the polyene-sterol pairs in solution, micelles, and in membranes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI017595-08
Application #
3127296
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1980-12-01
Project End
1991-11-30
Budget Start
1987-12-01
Budget End
1988-11-30
Support Year
8
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Virginia
Department
Type
Schools of Arts and Sciences
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Hartsel, S C; Perkins, W R; McGarvey, G J et al. (1988) A selective cholesterol-dependent induction of H+/OH- currents in phospholipid vesicles by amphotericin B. Biochemistry 27:2656-60