This overall goal of this research program is to develop new synthesis strategies and methods and use them to characterize the channel-based mechanism of action of amphotericin B (AmB) in atomistic detail, thereby enabling the rational optimization of the therapeutic index of this clinically-vital but also highly toxic antimycotic agent. Computer modeling studies predict that certain protic functional groups appended to the natural product are critical for self-assembly of the AmB/cholesterol channel (which leads to toxicity) but are not critical for the AmB/ergosterol channel (which leads to antifungal activity), thus leading to the following hypothesis: improvements in the therapeutic index of AmB can be achieved via the selective deletion of one or more of these protic functional groups. This research program aims to test this hypothesis systematically. New synthetic strategies and methods will be developed to enable the twelve protic functional groups appended to amphotericin B to be "deleted", one at a time. Analogous to the process of alanine scanning in protein science, the consequences of each protic functional group deletion will be determined in a battery of biophysical and biological assays. Statement in lay language: The antibiotic called "amphotericin" is the most effective medicine currently available for the treatment of life- threatening fungal infections. Unfortunately, however, this drug has many toxic side-effects that often limit its efficacy. This research program aims to understand more clearly how amphotericin works and minimize these toxic side-effects using a combination of organic synthesis and biological assays.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM080436-06S1
Application #
8659136
Study Section
Program Officer
Fabian, Miles
Project Start
2007-08-01
Project End
2017-01-31
Budget Start
2013-04-01
Budget End
2014-01-31
Support Year
6
Fiscal Year
2013
Total Cost
$78,765
Indirect Cost
$11,265
Name
University of Illinois Urbana-Champaign
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
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Woerly, Eric M; Roy, Jahnabi; Burke, Martin D (2014) Synthesis of most polyene natural product motifs using just 12 building blocks and one coupling reaction. Nat Chem 6:484-91
Woerly, Eric M; Miller, Jonathan E; Burke, Martin D (2013) (1-bromovinyl)-MIDA boronate: a readily accessible and highly versatile building block for small molecule synthesis. Tetrahedron 69:
Wilcock, Brandon C; Endo, Matthew M; Uno, Brice E et al. (2013) C2'-OH of amphotericin B plays an important role in binding the primary sterol of human cells but not yeast cells. J Am Chem Soc 135:8488-91
Dick, Graham R; Woerly, Eric M; Burke, Martin D (2012) A general solution for the 2-pyridyl problem. Angew Chem Int Ed Engl 51:2667-72
Gray, Kaitlyn C; Palacios, Daniel S; Dailey, Ian et al. (2012) Amphotericin primarily kills yeast by simply binding ergosterol. Proc Natl Acad Sci U S A 109:2234-9
Palacios, Daniel S; Dailey, Ian; Siebert, David M et al. (2011) Synthesis-enabled functional group deletions reveal key underpinnings of amphotericin B ion channel and antifungal activities. Proc Natl Acad Sci U S A 108:6733-8
Lee, Suk Joong; Anderson, Thomas M; Burke, Martin D (2010) A simple and general platform for generating stereochemically complex polyene frameworks by iterative cross-coupling. Angew Chem Int Ed Engl 49:8860-3
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Palacios, Daniel S; Anderson, Thomas M; Burke, Martin D (2007) A post-PKS oxidation of the amphotericin B skeleton predicted to be critical for channel formation is not required for potent antifungal activity. J Am Chem Soc 129:13804-5