Difference between revisions of "Kulkarni 2021 J Med Chem"

Revision as of 16:41, 14 January 2021

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 [Epub ahead of print].

» 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.

• Bioblast editor: Plangger M

Labels: MiParea: Respiration

HRR: Oxygraph-2k

2021-01

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 |year=2021
 |journal=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.
+|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<sup>+</sup>) moiety is the most widely used mitochondriotropic carrier. However, studies have shown that TPP+ is not inert; TPP<sup>+</sup> conjugates uncouple mitochondrial oxidative phosphorylation. To date, all efforts toward addressing this problem have focused on modifying lipophilicity of TPP<sup>+</sup>-linker-cargo conjugates to alter mitochondrial uptake, albeit with limited success. We show that structural modifications to the TPP<sup>+</sup> phenyl rings that decrease electron density on the phosphorus atom can abrogate uncoupling activity as compared to the parent TPP<sup>+</sup> 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<sup>+</sup> moiety as an inert mitochondria-targeting carrier to safely target pharmacophores and probes to mitochondria.
 |editor=[[Plangger M]]
 }}