Researchers at FAU combine chemistry and cell biology into an innovative tool for biomedical research

A key that only fits the lock when exposed to light – and even has additional tools at its disposal: Researchers at Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) involved in an interdisciplinary chemical-biological study have developed a versatile inhibitor. The molecular Swiss Army knife can be precisely activated with light, tracked in living cells, and expanded with additional functions. This opens up new possibilities for biomedical research, and, in the long term, for more precise medications. The study “A Multifunctional and Secure Photoresponsive Proteasome Inhibitor to Control Cell Fate” has been published in the Journal of the American Chemical Society*.

How can an active substance be controlled externally?

Ideally, medicine should only take effect where it is needed. In reality, this often proves difficult. Active substances spread throughout the body and, in addition to their intended target, can also affect healthy tissue and cause unwanted side effects. Prof. Dr. Henry Dube and Prof. Dr. Esther Zanin from FAU are therefore pursuing a different approach: They want to control the effect of a substance externally – using light.

What happens when the cell’s recycling machine comes to a standstill?

Dube is a chemist and develops molecules whose behavior can be controlled by light. Zanin is a cell biologist and studies the mechanisms and molecular processes behind how cells divide. For their current work, they have combined their expertise, together with Manuel Valentin (doctoral candidate in the Dube Lab) and David Féval (Master’s student in the Zanin Lab). The result is reminiscent of a Swiss Army knife in molecular form.

The starting point is an inhibitor called MG132. Its target is the proteasome, a type of recycling machine in every cell. It breaks down proteins that are no longer needed into their components, which can then be reused. This recycling is vital and also plays a crucial role in cell division. If the proteasome is blocked, central processes fall out of sync, ultimately leading to the death of the cell.

A light switch for a molecule? How does that work?

MG132 functions like a key that fits into a specific lock. It is this key that the researchers have now modified. “We essentially put a cap on it,” explains Prof. Dr. Henry Dube, Chair of Organic Chemistry I at FAU’s Department of Chemistry. “With this cap, the key no longer fits the lock, and the inhibitor remains inactive. Only when we irradiate it with light does the cap come off. The key fits again and can block the proteasome.”

The principle belongs to an emerging research field called photopharmacology. The idea: Active ingredients should not be constantly and universally active; instead, they should be activated as precisely as possible wherever and whenever their effect is required. In the long term, this could help, for instance, to spare healthy tissue when treating cancer. However, there is still a long way to go. At the current time, the researchers from Erlangen have focused on investigating the underlying principle in cells.

How reliably does the molecular “cap” stay in place?

They were able to demonstrate that their “cap” is unusually reliable at staying in place. Without light, the inhibitor remains inactive even over longer periods. After irradiation with light, however, it is released, blocking the proteasome and preventing the degradation of specific proteins. Ultimately, the treated cells die.

But the light switch is just one tool the molecular Swiss Army knife has at its disposal. Dube and Zanin have also incorporated a docking site for attaching additional molecular building blocks. In the study, they used a fluorescent dye that allowed them to use a microscope to track where their inhibitor is located in the living cell.

Light as a remote control for a cellular process

For Prof. Dr. Esther Zanin, Professorship for Experimental Molecular Cell Dynamics at FAU’s Department of Biology, this is the very point: “We can determine when our inhibitor should become active, but at the same time, we can also observe where it is located in the cell and what happens after it is activated. This gives us a precision tool that allows us to investigate biological processes with a high degree of control over time and place.”

One area where this is particularly interesting is for researching cell division. Cell division involves a number of precisely coordinated steps in which proteins are built up and then broken down again. A photo-responsive inhibitor can be used to deliberately interrupt this sequence at specific points. Light thus becomes, so to speak, a remote control for a biological process.

What else can be added to this molecular Swiss Army knife?

The fluorescent dye is just one initial example. Additional components could be coupled to the extra docking site in the future, for instance molecules that guide the inhibitor to specific areas of a cell, or possibly a second active ingredient. “If we attach something to our key, we must of course take care not to change it so much that it no longer fits the lock,” says Dube. “That is the challenge we face – but also the great potential of this modular system.”

A research tool today, the medication of tomorrow

There is still a long way to go before the research is ready for clinical use in patients. However, the benefits the molecule can already offer basic research today shouldn’t be underestimated. And the research is set to pave the way to even greater advances in the future. One day, active ingredients might not only be able to identify a target in the body, but could also be controlled externally, provide information about their location, and carry out additional functions.

Exploiting the synergies of merging chemistry and biology

Combining two research worlds paves the way for exciting new developments. “We come from very different fields,” says Zanin. “On the one hand, there’s chemistry, which can build and control such molecules in the first place. On the other hand, there’s biology, which can study the various functions of the Swiss Army knife in living cells. Only when both come together do such new possibilities emerge.”

*doi: https://doi.org/10.1021/jacs.6c10586

Further information:

Zanin Lab website: https://www.zelldynamik.nat.fau.de/

Dube Lab website: https://www.chemistry.nat.fau.eu/research/research-groups/dube-group/dube-group/

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