Jean-Yves Winum: a pure local product with global appeal

"I am a true product of Montpellier," jokes Jean-Yves Winum, whose accent leaves no doubt about his origins. The professor at the University of Montpellier studied and earned his doctorate in organic chemistry at the same institution. And it was there that he obtained his position as a lecturer at the age of 27, just after returning from his post-doctorate at Georgetown University (Washington, D.C.), barely a year after defending his thesis in 1998.

However, don't think that his horizons are limited to this southern city. A renowned chemist in the scientific community specializing in the modulation of carbonic anhydrase enzyme activity, theIBMM researcherhas forged numerous international collaborations. His contribution to research on these enzymes as a therapeutic target for cancer treatments and against pathogens earned him this year's Michel Delalande Prize from the French National Academy of Pharmacy.

Targeting carbonic anhydrases

Found in bacteria, plants, and animals, carbonic anhydrases are involved in numerous biological processes. "When I started working on these enzymes, some people considered them too common to be the key to therapeutic treatments, because their multitude of functions raised fears of too many side effects," recalls the chemist, who did not share this view. Together with his European colleagues, he identified AC9 and AC12 among the fourteen existing forms of carbonic anhydrases (CA) as being preferentially expressed in cancerous tumors and therefore priority targets.

"Our initial work on these carbonic anhydrases aimed to inhibit their activity within hypoxic solid tumors," explains Jean-Yves Winum. In tumors, these enzymes contribute to the acidification of the tumor microenvironment, which in turn promotes the spread of tumor cells and therefore metastasis. "Laboratory tests were conclusive: inhibiting these enzymes limited tumor expansion and breast tumor growth in vivo." These results were published in 2011 in Cancer Research in collaboration with other European teams, in particular the University of Florence.

Promising avenue for an antibacterial agent

The researcher also worked on another, more unexpected therapeutic target: carbonic anhydrases in Brucella, a bacterium that was feared at the time as a bioterrorism agent. "We were working with Stephan Köhler's team (IRIM) on inhibiting carbonic anhydrases in these pathogens in order to neutralize them," he explains (Brucella suis carbonic anhydrases and their inhibitors: towards alternative antibiotics?, 2017, in Journal of Enzyme Inhibition and Medicinal Chemistry).

Although interest in Brucella has waned, research into antibacterial modes of action remains strategic at a time when antibiotic resistance has become a major concern for the World Health Organization (WHO). "Inhibiting carbonic anhydrases in pathogens is a promising avenue for antibacterial treatment, even though we are still at the basic research stage. No treatment is currently in development," the chemist cautions.

The chemist's flair

"I develop strong collaborations. Trusting relationships are the best way to move forward," emphasizes Jean-Yves Winum, who stresses the need to be able to rely on a close-knit international scientific community. While his team in Montpellier works on the design and synthesis of inhibitors, the University of Florence conducts tests on enzymes, and other teams, particularly in the United States, carry out biological tests. "Some collaborations have led to strong friendships, such as with Claudiu Supuran from the University of Florence, with whom I have been working for over 20 years. We have co-authored more than 160 publications."

Molecular design has also evolved rapidly with improvements in X-ray structures: thanks to synchrotrons, researchers can observe enzyme-inhibitor interactions at the molecular level and improve their inhibitor molecules accordingly to make them as effective as possible. "We are moving towards a new generation of molecules that are more active and more selective," says the man who is convinced of the importance of a chemist's intuition. Proof of this is his latest award: "the distinction of a career in chemistry by the National Academy of Pharmacy," he says, without hiding his delight.

Escape games and board games

Since 2016, he has been developing a specific type of inhibitor in Montpellier that incorporates boron atoms, a mineral found naturally in soil, water, and food. "Several therapeutic compounds contain boron, so I thought it was worth trying on carbonic anhydrase inhibitors. And indeed, we have shown that it works very well! Another promising area of research on anti-cancer agents, developed in collaboration with Sébastien Clément ofthe ICGM, involves combining inhibitors with a photosensitizer. Under the effect of light, the photosensitizer produces singlet oxygen, which destroys cancer cells, an action that complements the inhibition.

In addition to his research, this man, whom some colleagues describe as hyperactive, holds several positions: deputy director of the Faculty of Science in charge of communication and scientific outreach, and deputy editor-in-chief of the Journal of Enzyme Inhibition and Medicinal Chemistry. Since 2020, he has also been involved in the gamification of teaching, developing escape games and board games as training aids (Serious games in organic chemistry: learning while having fun in college!). He has also co-authored six educational books. This work earned him the 2023 award from the Education and Training Division of the French Chemical Society.