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COPPERMAC
Mitochondrial copper targeting to modulate inflammatory macrophages
FunderFrench National Research Agency (ANR)
Funder Contribution €618,635.00
DurationFrom 01 Apr 2024
Project codeANR-23-CE44-0030
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Description
Excessive inflammation can occur in response to infection and is a hallmark of several diseases. Effective drugs against acute forms of inflammation are scarce. Our data reported an uptake of copper via CD44 by inflammatory macrophages. We identified that mitochondrial copper(II) catalyzes the reduction of hydrogen peroxide by NADH to replenish NAD+, an enzymatic cofactor required for the biosynthesis of key metabolites involved in the regulation of epigenetic landscapes. We developed a small molecule inhibitor, a biguanide analog of metformin, LCC-12, that selectively targets mitochondrial copper(II). Robust evidence from our laboratory validates that chelation of mitochondrial copper (II) by LCC-12 dampens the pro-inflammatory effects of macrophages, including at the level of gene expression signatures. Now, we will decipher and better characterize the mechanism of action of LCC-12 in vitro. Then, this proof-of-concept will be established in murine models of inflammatory diseases. This project identifying a novel drug to target copper in macrophages, will unveil a novel strategy to control inflammation.
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Excessive inflammation can occur in response to infection and is a hallmark of several diseases. Effective drugs against acute forms of inflammation are scarce. Our data reported an uptake of copper via CD44 by inflammatory macrophages. We identified that mitochondrial copper(II) catalyzes the reduction of hydrogen peroxide by NADH to replenish NAD+, an enzymatic cofactor required for the biosynthesis of key metabolites involved in the regulation of epigenetic landscapes. We developed a small molecule inhibitor, a biguanide analog of metformin, LCC-12, that selectively targets mitochondrial copper(II). Robust evidence from our laboratory validates that chelation of mitochondrial copper (II) by LCC-12 dampens the pro-inflammatory effects of macrophages, including at the level of gene expression signatures. Now, we will decipher and better characterize the mechanism of action of LCC-12 in vitro. Then, this proof-of-concept will be established in murine models of inflammatory diseases. This project identifying a novel drug to target copper in macrophages, will unveil a novel strategy to control inflammation.
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