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Decoding the journey of sulfur-containing molecules through cell membranes

ProfessorÌýStefan Matile and his group at the ÓñÃÀÈË´«Ã½ shed light on the molecular mechanisms of thiol-mediated uptake (TMU). TMU is the process governing cellular entry of sulfur-containing molecules. Their study, funded byÌýanÌýSNSF Advanced Grant awarded to ProfessorÌýMatile in 2022 and published in , identifies the specific partners on cell surfacesÌýwith which interact a set of sulfur-containing molecules denotedÌýcascade exchangers (CAXs). The article shows the existence of orthogonal exchange networks between specific CAX motifs and membrane proteins. The research should pave the way for the development of new targeted drug delivery systems and cell-entry inhibitor drugs.

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The sulfur-containing molecules CAX1, CAX2 and CAX3 interact with different membrane proteins resulting in orthogonal penetration pathways. Credits: UNIGE/Matile.

ENTERING CELLS: A COMPLEX JOURNEY

The journey trough cell membranesÌýis a highly regulated biochemical process. Whether it is a chemist aiming to target cellular proteins with drugs, or a virus seeking to penetrate cells for replication, or a scientist seeking to prevent viral entry, they all require to penetrate cell membranes. Thus, understanding and controlling the mechanisms of cell penetration is crucial.

ProfessorÌýStefan Matile, from the Department of Organic Chemistry at theÌýFaculty of Science of theÌýÓñÃÀÈË´«Ã½, has long been captivated by chemical reactions involving sulfur atoms, abundant in cellular membranes. Particularly, he focused on thiol-mediated uptake (TMU), a process where sulfur-containing molecules can traverse cell membranes through a series of covalent exchanges with membrane proteins. In the past, ProfessorÌýMatile introduced a family of sulfur-containing molecules, denotedÌýcascade exchangers (CAXs), that efficiently go though the cell membrane. Notably, he showed that some CAXs can be used to inhibit the entry ofÌývirus modelsÌýinto cells,ÌýhighlightingÌýtheÌýpotentialÌýof TMU to develop antiviral drugs.

A mechanism still to be discovered.

Despite its significance, the molecular mechanism of TMU is still unknown. In their recent article, published in , ProfessorÌýMatile and his group developed a general protocol that can be used to understandÌýTMU networks. They identified the membrane partners responsible for TMU. They found that the different CAXs interact withÌýdistinct membrane proteins, thus showing the existence of orthogonal exchange networks. This project is a major objective of ProfessorÌýMatile’sÌýSNSF Advanced Grant.Ìý

In this new , theÌýresearch team developpedÌýaÌýmethod that can identify which exchange membrane interact with which CAXs. These networks include multiple exchange partners on the cell surface. Importantly here, the researchers examinatedÌýfour exchange membrane protein partners and found that each couldÌýbeassignedÌýtoÌýdifferent existingÌýCAXs. This specificity is particularly important as it resultsÌýin the orthogonality of these different exchange networks.Ìý

"Our research offers unprecedented insights into the intricate molecular machinery driving TMU"Ìýremarks Professor Stefan Matile. "By deciphering these exchange networks, we are closer to comprehending how substances traverse cell membranes via thiol-mediated uptake."

Understanding the different pathways of TMU holds promise for advancing drug delivery systems and also to develop virus entry inhibitors. Combining the previously introduced, and still growing, CAX family, to the precise identification of theirÌýexchangeÌýwith transmembrane proteins, the prospect of controlling drug entry or inhibiting specific pathogenic pathways becomes tangible.

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Watch Prof. Stefan Matile presenting his researchÌý