Sec61 Inhibitors

Chemical inhibitors of Sec61 can exert their inhibitory effects through various mechanisms, targeting the protein's role in translocation of polypeptides into the endoplasmic reticulum (ER). Eeyarestatin I directly binds to Sec61, disrupting its function and thus blocking the activity of the translocon complex, essential for protein translocation into the ER. Similarly, Cotransin selectively blocks the Sec61 translocon by binding to the Sec61α subunit, which is a critical action for preventing the insertion of nascent polypeptides into the ER membrane. Apratoxin A, by altering the lipid environment of Sec61, hinders Sec61-mediated import of proteins into the ER, thus inhibiting the translocation process. Ipomoeassin F binds to Sec61, obstructing the translocon pore and impeding the proper functioning of the Sec61 complex. Mycolactone and HUN-7293 also target Sec61, with mycolactone binding to the protein and blocking its translocation channel activity, while HUN-7293 is believed to interact with the Sec61α subunit, impairing the protein conduction channel.

The inhibition of Sec61 can also occur as an indirect consequence of the inhibition of other cellular processes. Exotoxin A and Ricin, for example, do not directly interact with Sec61 but lead to its inhibition by targeting elongation factor-2 (EF-2) and ribosomes, respectively. Exotoxin A ADP-ribosylates and inactivates EF-2, which is vital for protein synthesis, and consequently, Sec61-dependent translocation is hindered as protein synthesis is halted. Ricin depurinates a specific adenine residue in the ribosomes, resulting in the inactivation of ribosomes and an indirect inhibition of Sec61's role in protein translocation due to the cessation of protein synthesis. Bouvardin and Lycorine inhibit protein synthesis by affecting ribosomes and translation elongation, respectively, leading to a decrease in the availability of polypeptide substrates for the Sec61 translocation process. This array of chemicals demonstrates the diverse ways in which Sec61 can be inhibited, either through direct binding and interaction or as a result of the inhibition of upstream processes essential for its function.