Journal article
A Novel Triphenylphosphonium Carrier to Target Mitochondria without Uncoupling Oxidative Phosphorylation
Journal of medicinal chemistry, Vol.64(1), pp.662-676
01/14/2021
DOI: 10.1021/acs.jmedchem.0c01671
PMCID: PMC8293692
PMID: 33395531
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.
Details
- Title: Subtitle
- A Novel Triphenylphosphonium Carrier to Target Mitochondria without Uncoupling Oxidative Phosphorylation
- Creators
- Chaitanya A Kulkarni - University of IowaBrian D Fink - University of IowaBettine E Gibbs - University of IowaPratik R Chheda - University of IowaMeng Wu - University of IowaWilliam I Sivitz - University of IowaRobert J Kerns - Division of Medicinal and Natural Products Chemistry, Department of Pharmaceutical Sciences and Experimental Therapeutics
- Resource Type
- Journal article
- Publication Details
- Journal of medicinal chemistry, Vol.64(1), pp.662-676
- DOI
- 10.1021/acs.jmedchem.0c01671
- PMID
- 33395531
- PMCID
- PMC8293692
- NLM abbreviation
- J Med Chem
- ISSN
- 0022-2623
- eISSN
- 1520-4804
- Publisher
- American Chemical Society
- Grant note
- DOI: 10.13039/100000738, name: U.S. Department of Veterans Affairs, award: 2 I01 BX000285-05; DOI: 10.13039/100000968, name: American Heart Association, award: 19POST34380212; DOI: 10.13039/100008893, name: University of Iowa; name: Iowa State Fraternal Order of the Eagles; name: College of Pharmacy, University of Iowa
- Language
- English
- Date published
- 01/14/2021
- Academic Unit
- Pharmacy; Pharmaceutical Sciences and Experimental Therapeutics; Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Medicinal and Natural Products Chemistry; Internal Medicine
- Record Identifier
- 9984366033102771
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