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Cell Res. 2009 May;19(5):625-37. doi: 10.1038/cr.2009.17.

From the Gla domain to a novel small-molecule detector of apoptosis.

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1
Aposense Ltd, 5-7 Ha'Odem St, Kiryat Matalon, PO Box 7119, Petach Tikva, Israel. avi@aposense.com

Erratum in

  • Cell Res. 2011 Nov;21(11):1642.

Abstract

Apoptosis plays a pivotal role in the etiology or pathogenesis of numerous medical disorders, and thus, targeting of apoptotic cells may substantially advance patient care. In our quest for novel low-molecular-weight probes for apoptosis, we focused on the uncommon amino acid gamma-carboxyglutamic acid (Gla), which plays a vital role in the binding of clotting factors to negatively charged phospholipid surfaces. Based on the alkyl-malonic acid motif of Gla, we have developed and now present ML-10 (2-(5-fluoro-pentyl)-2-methyl-malonic acid, MW=206 Da), the prototypical member of a novel family of small-molecule detectors of apoptosis. ML-10 was found to perform selective uptake and accumulation in apoptotic cells, while being excluded from either viable or necrotic cells. ML-10 uptake correlates with the apoptotic hallmarks of caspase activation, Annexin-V binding and disruption of mitochondrial membrane potential. The malonate moiety was found to be crucial for ML-10 function in apoptosis detection. ML-10 responds to a unique complex of features of the cell in early apoptosis, comprising irreversible loss of membrane potential, permanent acidification of cell membrane and cytoplasm, and preservation of membrane integrity. ML-10 is therefore the most compact apoptosis probe known to date. Due to its fluorine atom, ML-10 is amenable to radio-labeling with the (18)F isotope, towards its potential future use for clinical positron emission tomography imaging of apoptosis.

PMID:
19223854
DOI:
10.1038/cr.2009.17
[Indexed for MEDLINE]
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