Small molecules that imperfectly replicate protein function of missing proteins restore physiology in yeast and human epithelia
type: CreativeWork
description: Human diseases caused by an excess of protein function can often be treated with small molecules that bind and inhibit the corresponding proteins. In contrast, there are many currently incurable human diseases that are caused by missing protein ion transporters, including cystic fibrosis and microcytic anemia. Like many other human diseases caused by missing proteins, these diseases are difficult to treat, and new approaches are needed. Some small molecules can perform ion transporter-like functions, suggesting the possibility of replacing missing protein ion transporters with small molecule mimics. Closely replicating the functions of ion selective and tightly regulated protein transporters with small molecules is challenging. However, robust protein networks comprised of pumps and channels drive targeted ions in targeted directions throughout the spectrum of living systems. We hypothesized that relatively unselective and unregulated small molecule mimics of missing protein transporters might be capable of collaborating with the corresponding protein ion pumps to restore physiology. The ion channel-forming natural product amphotericin B (AmB) was first identified as a small molecule that could enable testing of this hypothesis. AmB is the prototypical small molecule capable of ion channel formation and can permeabilize both yeast and human cells to potassium and other ions. We observed vigorous and sustainable restoration of yeast cell growth by replacing potassium ion transporters with AmB. We next tested whether AmB could restore physiology in cystic fibrosis (CF) human lung epithelia. We observed restoration of key makers of physiology in CF epithelia upon treatment with AmB. Chemical inhibition experiments demonstrated evidence for collaboration between AmB and protein ion pumps in both yeast and human epithelia. To fully harness the ion channel property of AmB in the setting of protein deficiencies, a detailed understanding of how AmB interacts with membranes …
abstract: Human diseases caused by an excess of protein function can often be treated with small molecules that bind and inhibit the corresponding proteins. In contrast, there are many currently incurable human diseases that are caused by missing protein ion transporters, including cystic fibrosis and microcytic anemia. Like many other human diseases caused by missing proteins, these diseases are difficult to treat, and new approaches are needed. Some small molecules can perform ion transporter-like functions, suggesting the possibility of replacing missing protein ion transporters with small molecule mimics. Closely replicating the functions of ion selective and tightly regulated protein transporters with small molecules is challenging. However, robust protein networks comprised of pumps and channels drive targeted ions in targeted directions throughout the spectrum of living systems. We hypothesized that relatively unselective and unregulated small molecule mimics of missing protein transporters might be capable of collaborating with the corresponding protein ion pumps to restore physiology. The ion channel-forming natural product amphotericin B (AmB) was first identified as a small molecule that could enable testing of this hypothesis. AmB is the prototypical small molecule capable of ion channel formation and can permeabilize both yeast and human cells to potassium and other ions. We observed vigorous and sustainable restoration of yeast cell growth by replacing potassium ion transporters with AmB. We next tested whether AmB could restore physiology in cystic fibrosis (CF) human lung epithelia. We observed restoration of key makers of physiology in CF epithelia upon treatment with AmB. Chemical inhibition experiments demonstrated evidence for collaboration between AmB and protein ion pumps in both yeast and human epithelia. To fully harness the ion channel property of AmB in the setting of protein deficiencies, a detailed understanding of how AmB interacts with membranes …
author: Cioffi, Alexander Geoffrey
language: en
keywords: Ion channels, Natural products
date published: 2017-08-10T19:51:34Z
date modified: 2026-07-22T22:24:34Z
provider: University of Illinois - Urbana-Champaign
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Illinois at Urbana-Champaign

PropertyValue
property ID: Handle
value: http://hdl.handle.net/2142/97529