Designing a drug to target metals in cells

Intelligent drug design is challenging, but mechanistic clues can greatly help in this process. Metformin forms bimolecular complexes with Cu(II) and we designed a molecule linking two metformin moieties together with a linker to create a much more potent drug in a study now published in Nature.
Designing a drug to target metals in cells
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Our previous work1 on persister cancer cells made us wonder if CD44 could play a role in metal import in other cell types and regulate cell plasticity in a wide spectrum of cells. We set out to study this process in macrophages derived from primary monocytes isolated from blood. Using this system, we found that during inflammatory macrophage activation, cells predominantly take up metals via CD44, including copper, iron, calcium and magnesium2. Interestingly, canonical copper transporters had a marginal effect on copper uptake. Then, we set out to investigate the effect of metals on cell plasticity in macrophages, with a particular focus on copper.

We identified metformin to have an effect on cell plasticity in cancer and macrophages. Metformin was reported back in 1929 to form complexes with Cu(II)3 and we previously observed that it accumulates in mitochondria4. Since metformin forms a 2:1 complex with Cu(II) we designed a new molecule - we later termed supformin - which links two biguanides together with a linker. This changes the inherent entropic effect and in fine has a potency 5000 more elevated than metformin in interfering with cell plasticity. 

Structures of metformin and supformin and respective complexes with Cu(II).

What are the effects of copper chelation?

We found that supformin can reprogram cell metabolism in macrophages and reduce total NAD(H) levels. Since these metabolites are crucial for many metabolic processes, including the Krebs cycle, we observed altered levels of several metabolites, of which acetyl-CoA and alpha-ketoglutarate stood out. These two metabolites are crucial for histone demethylation and acetylation in the cell nucleus, thus, changing their levels will ultimately lead to changes in the epigenetic landscape of the cell. Changes of the epigenetic landscape are inherent with changes in cell phenotype. Indeed, supformin treatment lead to epigenetic reprogramming into a less inflammatory state.

Finally, this was also observed in animal models of sepsis, where we could rescue survival of mice.

Rescue of mice in animal models of sepsis.

This work is, in our opinion, a good example of how chemical biology and the understanding of chemical reactivity can lead to major discoveries in cell biology. 

Our working model of CD44-mediated metal endocytosis.

References

1 Nat Chem. 2020 Oct;12(10):929-938. doi: 10.1038/s41557-020-0513-5

2 Nature. 2023 May;617(7960):386-394. doi: 10.1038/s41586-023-06017-4

3 Ber. dt. chem. Ges. 1929, 1390–1398. doi: 10.1002/cber.19290620604

4 PLoS One. 2018 Nov 6;13(11):e0206764. doi: 10.1371/journal.pone.0206764

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