Kulkarni 2021 J Med Chem

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Kulkarni CA, Fink BD, Gibbs BE, Chheda PR, Wu M, Sivitz WI, Kerns RJ (2021) A novel triphenylphosphonium carrier to target mitochondria without uncoupling oxidative phosphorylation. J Med Chem 64:662-76.

» PMID: 33395531

Kulkarni CA, Fink BD, Gibbs BE, Chheda PR, Wu M, Sivitz WI, Kerns RJ (2021) J Med Chem

Abstract: Mitochondrial dysfunction is an underlying pathology in numerous diseases. Delivery of diagnostic and therapeutic cargo directly into mitochondria is a powerful approach to study and treat these diseases. The triphenylphosphonium (TPP+) moiety is the most widely used mitochondriotropic carrier. However, studies have shown that TPP+ is not inert; TPP+ conjugates uncouple mitochondrial oxidative phosphorylation. To date, all efforts toward addressing this problem have focused on modifying lipophilicity of TPP+-linker-cargo conjugates to alter mitochondrial uptake, albeit with limited success. We show that structural modifications to the TPP+ phenyl rings that decrease electron density on the phosphorus atom can abrogate uncoupling activity as compared to the parent TPP+ moiety and prevent dissipation of mitochondrial membrane potential. These alterations of the TPP+ structure do not negatively affect the delivery of cargo to mitochondria. Results here identify the 4-CF3-phenyl TPP+ moiety as an inert mitochondria-targeting carrier to safely target pharmacophores and probes to mitochondria.


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2021-01