Decoding the journey of sulfur-containing molecules through cell membranes

Professor Stefan Matile and his group at the University of Geneva 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 by an SNSF Advanced Grant awarded to Professor Matile in 2022 and published in ACS Central Science, identifies the specific partners on cell surfaces with which interact a set of sulfur-containing molecules denoted cascade 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.

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 membranes is 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.

Professor Stefan Matile, from the Department of Organic Chemistry at the Faculty of Science of the University of Geneva, 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, Professor Matile introduced a family of sulfur-containing molecules, denoted cascade exchangers (CAXs), that efficiently go though the cell membrane. Notably, he showed that some CAXs can be used to inhibit the entry of virus models into cells, highlighting the potential of 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 ACS Central Science, Professor Matile and his group developed a general protocol that can be used to understand TMU networks. They identified the membrane partners responsible for TMU. They found that the different CAXs interact with distinct membrane proteins, thus showing the existence of orthogonal exchange networks. This project is a major objective of Professor Matile’s SNSF Advanced Grant. 

In this new publication, the research team developped a method that can identify which exchange membrane interact with which CAXs. These networks include multiple exchange partners on the cell surface. Importantly here, the researchers examinated four exchange membrane protein partners and found that each could beassigned to different existing CAXs. This specificity is particularly important as it results in the orthogonality of these different exchange networks. 

"Our research offers unprecedented insights into the intricate molecular machinery driving TMU" remarks 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 their exchange with transmembrane proteins, the prospect of controlling drug entry or inhibiting specific pathogenic pathways becomes tangible.

Watch Prof. Stefan Matile presenting his research