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De Novo Development of Mitochondria-Targeted Molecular Probes Targeting Pink1

Authors :
Shulamit Fluss Ben-Uliel
Faten Habrat Zoabi
Moriya Slavin
Hadas Sibony-Benyamini
Nir Kalisman
Nir Qvit
Source :
International Journal of Molecular Sciences, Vol 23, Iss 11, p 6076 (2022)
Publication Year :
2022
Publisher :
MDPI AG, 2022.

Abstract

Mitochondria play central roles in maintaining cellular metabolic homeostasis, cell survival and cell death, and generate most of the cell’s energy. Mitochondria maintain their homeostasis by dynamic (fission and fusion) and quality control mechanisms, including mitophagy, the removal of damaged mitochondria that is mediated mainly by the Pink1/Parkin pathway. Pink1 is a serine/threonine kinase which regulates mitochondrial function, hitherto many molecular mechanisms underlying Pink1 activity in mitochondrial homeostasis and cell fate remain unknown. Peptides are vital biological mediators that demonstrate remarkable potency, selectivity, and low toxicity, yet they have two major limitations, low oral bioavailability and poor stability. Herein, we rationally designed a linear peptide that targets Pink1 and, using straightforward chemistry, we developed molecular probes with drug-like properties to further characterize Pink1. Initially, we conjugated a cell-penetrating peptide and a cross-linker to map Pink1’s 3D structure and its interaction sites. Next, we conjugated a fluorescent dye for cell-imaging. Finally, we developed cyclic peptides with improved stability and binding affinity. Overall, we present a facile approach to converting a non-permeable linear peptide into a research tool possessing important properties for therapeutics. This is a general approach using straightforward chemistry that can be tailored for various applications by numerous laboratories.

Details

Language :
English
ISSN :
14220067 and 16616596
Volume :
23
Issue :
11
Database :
Directory of Open Access Journals
Journal :
International Journal of Molecular Sciences
Publication Type :
Academic Journal
Accession number :
edsdoj.602a166b79574b48a680c3ca72e46484
Document Type :
article
Full Text :
https://doi.org/10.3390/ijms23116076