Volume 19, No 5, May 2009
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 19 Issue 5, May 2009: 625-637
ORIGINAL ARTICLES
From the Gla domain to a novel small-molecule detector of apoptosis
Avi Cohen*, Anat Shirvan*, Galit Levin, Hagit Grimberg, Ayelet Reshef, Ilan Ziv
Aposense Ltd, 5-7 Ha扥dem St, Kiryat Matalon, PO Box 7119, Petach Tikva, Israel
Correspondence: Avi Cohen(avi@aposense.com)
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 γ-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 radiolabeling with the 18F isotope, towards its potential future use for clinical positron emission tomography imaging of apoptosis.
Cell Research (2009) 19:625–637. doi: 10.1038/cr.2009.17; published online 17 February 2009
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