Apoptosis plays a pivotal role in the etiology or pathogenesis of numerous medical disorders, and thus, target- ing of apoptotic cells may substantially advance patient care. In our quest for novel low-molecular-weigh...Apoptosis plays a pivotal role in the etiology or pathogenesis of numerous medical disorders, and thus, target- ing 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 T-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 pro- totypical 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 lSF isotope, towards its potential future use for clinical positron emission tomography imaging of apoptosis.展开更多
文摘Apoptosis plays a pivotal role in the etiology or pathogenesis of numerous medical disorders, and thus, target- ing 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 T-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 pro- totypical 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 lSF isotope, towards its potential future use for clinical positron emission tomography imaging of apoptosis.
