Pharmaceutically acceptable phosphorylation state modulator of at least one enzyme and / or enzyme complex, or subunits thereof, in mitochondria of diseased cells of warm-blooded animals, including humans, method of modulating at least one enzyme or enzyme complex , or a subunit thereof, in a patient having a disease, condition, or syndrome including a change in the phosphorylation state of at least one enzyme and / or an enzyme complex, or a subunit thereof, and method to diagnose and predict benefit in a patient who has symptoms of a disease, condition, or syndrome that includes a change in
ROBERT SHORR,ROBERT RODRIGUEZ,PAUL BINGHAM,LAKA W. BOTEJU,ZUZANA ZACHAR
申请号：
BRPI0821894
公开号：
BRPI0821894A2
申请日:
2008.04.04
申请国别(地区):
BR
年份:
2015
代理人:
摘要：
A pharmaceutically-acceptable modulator of the regulation or perturbation of the structure, expression, and/or activity of at least one enzyme and/or enzyme complex, or subunit thereof, such as via the altered mitochondrial energy metabolism of the pyruvate dehydrogenase (PDH) complex of warm-blooded animals, including humans, and methods of use thereof, comprises an effective amount of at least one lipoic acid derivative and at least one pharmaceutically-acceptable carrier thereof to affect the complex's phosphorylation state. By increasing PDH kinase activity and/or decreasing PDH phosphatase activity, the modulator prevents the detoxification anaerobic glycolytic toxic metabolites through inhibition of the activity of the PDH complex's El a subunit, obliging increased mitochondrial oxidative phosphorylation activity. As cells characterized by hyperproliferation, such as tumor cells, cannot also generate acetyl-CoA and NADH because of the modulator's additional action in inhibiting the action of the PDH complex's E2 subunit, the mitochondrial membrane polarization is lost, facilitating cell death.
