Virginia Tech
Design and Synthesis of Mitochondrial Uncouplers for the Treatment of Mitochondrial Dysfunction
Abstract
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.
Degree
thesis:*- Name thesis:degree_name
- Doctor of Philosophy
- Level thesis:degree_level
- doctoral
- Discipline thesis:degree_discipline
- Chemistry
- Department dc:contributor.department
- Chemistry
- Grantor dc:publisher
- Virginia Tech
- Year dc:date.issued
- 2025
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Foutz, Mary Abigail
- Chair dc:contributor.committeechair
-
- Santos, Webster
- Committee members dc:contributor.committeemember
-
- Tanko, James M.
- Lowell, Andrew Nesemann
- Mevers, Emily Elizabeth
Subjects
dc:subject × 7Rights
dc:rights- Statement dc:rights
-
- In Copyright
- Licence dc:rights.uri
- Language dc:language.iso
- en
Identifiers
dc:identifier.*- Dc Identifier Other
- vt_gsexam:42932
- OAI identifier oai:identifier
- oai:vtechworks.lib.vt.edu:10919/129384