Design and Synthesis of Mitochondrial Uncouplers for the Treatment of Mitochondrial Dysfunction

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dc.contributor.authorFoutz, Mary Abigailen
dc.contributor.committeechairSantos, Websteren
dc.contributor.committeememberTanko, James M.en
dc.contributor.committeememberLowell, Andrew Nesemannen
dc.contributor.committeememberMevers, Emily Elizabethen
dc.contributor.departmentChemistryen
dc.date.accessioned2025-05-07T08:01:58Zen
dc.date.available2025-05-07T08:01:58Zen
dc.date.issued2025-05-06en
dc.description.abstractgeneralWithin the body, mitochondrial has a leading role in many cellular functions including energy production and cell signaling. When mitochondria become dysfunctional diseases such as obesity, type II diabetes mellitus, and metabolic dysfunction-associated steatohepatitis can occur. Mitochondrial dysfunction may be naturally mitigated by uncoupled respiration facilitated by membrane bound uncoupling proteins. Uncoupling proteins create leaks in the inner mitochondrial membrane (IMS), shuttling protons against the electrochemical gradient independent of ATP production. Another manner of uncoupling respiration is by using small molecule mitochondrial uncouplers that mimic the function of uncoupling proteins by shuttling protons across the membrane. Our lab has focused on synthesis of small molecule uncouplers to treat mitochondrial dysfunction. We use a potent and effective uncoupler, BAM15, as the basis for our design. BAM15 has been shown to effectively combat mitochondrial dysfunction in diseases models such as obesity. However, we are working on a redesign for improved druglike properties, such as half-life. Herein, we show the development of a new generation of small molecule uncouplers with pyridine cores that are efficacious in a Gubra-Amylin (GAN) mouse model of MASH. We also disclose a novel prodrug approach for BAM15 by utilizing a glyoxal cage. In doing so, we aim to achieve an improved pharmacokinetic property. These developments showcase the potential use of a mitochondrial uncouplers for the treatment of mitochondrial dysfunction and metabolic disease.en
dc.description.degreeDoctor of Philosophyen
dc.format.mediumETDen
dc.identifier.othervt_gsexam:42932en
dc.identifier.urihttps://hdl.handle.net/10919/129384en
dc.language.isoenen
dc.publisherVirginia Techen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectMitochondrial Uncouplersen
dc.subjectObesityen
dc.subjectMetabolismen
dc.subjectCellular Respirationen
dc.subjectMASHen
dc.subjectDiabetesen
dc.subjectMitochondrial Dysfunctionen
dc.titleDesign and Synthesis of Mitochondrial Uncouplers for the Treatment of Mitochondrial Dysfunctionen
dc.typeDissertationen
thesis.degree.disciplineChemistryen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.leveldoctoralen
thesis.degree.nameDoctor of Philosophyen

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