2026-09-22T22:07:38Z https://www.ideals.illinois.edu/oai-pmh

oai:www.ideals.illinois.edu:2142/127475 2026-02-03 col_2142_5131 col_2142_14789 com_2142_5130 com_2142_14788 com_2142_8903

application/pdf en text Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2026-12-01 The student, Johnnathan Marin-Toledo, accepted the attached license on 2024-11-26 at 10:28. The student, Johnnathan Marin-Toledo, submitted this Dissertation for approval on 2024-11-26 at 10:28. This Dissertation was approved for publication on 2024-12-04 at 12:14. DSpace SAF Submission Ingestion Package generated from Vireo submission #21398 on 2025-03-28 at 14:55:24 Development of second-generation amphotericin B molecular prosthetics for enhanced therapeutic efficacy in cystic fibrosis Marin-Toledo, Johnnathan P 2024-12-04 Burke, Martin D Burke, Martin D Hergenrother, Paul Mehta, Angad Grosman, Claudio Amphotericin B Cystic Fibrosis Cftr Anion-selective eng 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). 2024-12 Thesis https://hdl.handle.net/2142/127475 Copyright 2024 Jonnathan P. Marin-Toledo Chemistry Chemistry University of Illinois at Urbana-Champaign Ph.D. Dissertation