The mitochondrial permeability transition pore (mPTP), a high-conductance channel triggered by a sudden Ca(2+)concentration increase, is composed of the F1FO-ATPase. Since mPTP opening leads to mitochondrial dysfunction, which is a feature of many diseases, a great pharmacological challenge is to find mPTP modulators. In our study, the effects of two 1,5-disubstituted 1,2,3-triazole derivatives, five-membered heterocycles with three nitrogen atoms in the ring and capable of forming secondary interactions with proteins, were investigated. Compounds3aand3bwere selected among a wide range of structurally related compounds because of their chemical properties and effectiveness in preliminary studies. In swine heart mitochondria, both compounds inhibit Ca2+-activated F1FO-ATPase without affecting F-ATPase activity sustained by the natural cofactor Mg2+. The inhibition is mutually exclusive, probably because of their shared enzyme site, and uncompetitive with respect to the ATP substrate, since they only bind to the enzyme-ATP complex. Both compounds show the same inhibition constant (KMODIFIER LETTER PRIMEi), but compound3ahas a doubled inactivation rate constant compared with compound3b. Moreover, both compounds desensitize mPTP opening without altering mitochondrial respiration. The results strengthen the link between Ca2+-activated F1FO-ATPase and mPTP and suggest that these inhibitors can be pharmacologically exploited to counteract mPTP-related diseases.

1,5-Disubstituted-1,2,3-triazoles as inhibitors of the mitochondrial Ca2+ -activated F1 FO -ATP(hydrol)ase and the permeability transition pore

Algieri, Cristina
Co-primo
;
Pagliarani, Alessandra;Trombetti, Fabiana;Nesci, Salvatore
Ultimo
Supervision
2021

Abstract

The mitochondrial permeability transition pore (mPTP), a high-conductance channel triggered by a sudden Ca(2+)concentration increase, is composed of the F1FO-ATPase. Since mPTP opening leads to mitochondrial dysfunction, which is a feature of many diseases, a great pharmacological challenge is to find mPTP modulators. In our study, the effects of two 1,5-disubstituted 1,2,3-triazole derivatives, five-membered heterocycles with three nitrogen atoms in the ring and capable of forming secondary interactions with proteins, were investigated. Compounds3aand3bwere selected among a wide range of structurally related compounds because of their chemical properties and effectiveness in preliminary studies. In swine heart mitochondria, both compounds inhibit Ca2+-activated F1FO-ATPase without affecting F-ATPase activity sustained by the natural cofactor Mg2+. The inhibition is mutually exclusive, probably because of their shared enzyme site, and uncompetitive with respect to the ATP substrate, since they only bind to the enzyme-ATP complex. Both compounds show the same inhibition constant (KMODIFIER LETTER PRIMEi), but compound3ahas a doubled inactivation rate constant compared with compound3b. Moreover, both compounds desensitize mPTP opening without altering mitochondrial respiration. The results strengthen the link between Ca2+-activated F1FO-ATPase and mPTP and suggest that these inhibitors can be pharmacologically exploited to counteract mPTP-related diseases.
Algieri, Vincenzo; Algieri, Cristina; Maiuolo, Loredana; De Nino, Antonio; Pagliarani, Alessandra; Tallarida, Matteo Antonio; Trombetti, Fabiana; Nesci, Salvatore
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/797550
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