Development of second-generation amphotericin B molecular prosthetics for enhanced therapeutic efficacy in cystic fibrosis

Using small molecules, molecular prosthetics (MPs) to replace the function of missing or dysfunctional proteins as a therapeutic strategy to treat genetic disorders has made great strides over the years. In particular, for channelopathies, Amphotericin B (AmB), an ion channel-forming small molecule, has shown promise and surprising versatility as an MP by effectively replacing potassium-selective ion channels in yeast and bicarbonate-selective ion channels in human airway epithelial models. Despite its cation-permeable nature, AmB remains somewhat permeable to anions, although not to a high degree, which allows for this versatility. However, in this thesis, we explore the limitations of this versatility and develop strategies to overcome them to generate a next generation of AmB-based MPs that better replace individual ion channels. A series of AmB derivatives were rationally designed and synthetically prepared to study the ion selectivity, conductance, and toxic properties of the next generation of MPs using new electrophysiological and pre-clinical therapeutic models. These studies led to the discovery of the anion-selective MP, AmB-AA, which demonstrated superior performance compared to AmB and reduced the homeostatic burden that a cation-permeable molecule like AmB was causing in CF models. Additionally, these derivatives helped highlight key properties of the AmB ion channels, providing insight into the mechanism that enabled the development of a next generation AmB-based, epithelial-sparing, anion-selective molecular prosthetic, C2’epiAmB-AA, for the treatment of Cystic Fibrosis (CF).

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2024

Author dc:creator

• Marin-Toledo, Johnnathan P

Contributors dc:contributor

• Burke, Martin D
• Hergenrother, Paul
• Mehta, Angad
• Grosman, Claudio

• Amphotericin B
• Cystic Fibrosis
• Cftr
• Anion-selective

Statement dc:rights

• Copyright 2024 Jonnathan P. Marin-Toledo

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/127475

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F127475