Molecular Mechanism of Cotransin, a Potent and Selective Inhibitor of Protein Secretion

TL;DRAbstract

Secreted and transmembrane proteins represent the majority of current drug targets and play a dominant role in pathophysiological processes such as inflammation, angiogenesis, and metastasis. However, most secreted proteins and many transmembrane receptors are difficult to target with small‐molecule drugs. We recently synthesized a small molecule, termed “cotransin”, which potently inhibits the expression of a subset of secreted and transmembrane proteins, including the pro‐inflammatory cell adhesion molecule, VCAM. Cotransin is structurally related to the cyclodepsipeptide natural product, HUN‐7293. We discovered that cotransin blocks the cotranslational translocation of nascent VCAM chains into the endoplasmic reticulum, whereas it has no effect on the majority of secreted proteins. By a mechanism that is not yet clear, cotransin interferes with the ability of the Sec61 channel to open in response to a subset of signal sequences. Cotransin, HUN‐7293, and their structural variants off

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