We launched our research program with the search for small molecule replacements for missing proteins that underlie currently incurable human diseases. This pursuit drew us to amphotericin B, a remarkable natural product that is the archetype for ion-channel-forming small molecules. We quickly realized, however, that there was a second very important reason to study this natural product, as it represents the most powerful, broad-spectrum, and resistance-evasive treatment for invasive fungal infections, which still kill more than 1.5 million people each year - more than malaria or tuberculosis. The problem with amphotericin B is that it is highly toxic to humans, which limits the dose that can be administered. Through an extensive series of synthesis-enabled studies, we came to understand that, in contrast to the long-standing mechanistic model, amphotericin B kills yeast by simply binding ergosterol - channel formation is not required. This allowed us to focus squarely on the actionable problem of selectively binding ergosterol over cholesterol en route to an improved therapeutic index. This journey has yielded new types of amphotericin derivatives that bind ergosterol but not (detectably) cholesterol, and kill yeast but are substantially less toxic than amphotericin B in vitro and in vivo. This advanced mechanistic understanding has also brightened the prospect of developing small molecules that replace missing protein ion channels, thereby operating as prostheses on the molecular scale.
- N -methyliminodiacetic acid boronates
- protein-like functions
- small molecules
ASJC Scopus subject areas
- Organic Chemistry