Sar1 Inhibitors

Chemical inhibitors of Sar1 can disrupt its role in vesicle trafficking through various mechanisms. Brefeldin A, for instance, targets the ADP-ribosylation factor (ARF), a GTPase necessary for the formation of vesicles from the endoplasmic reticulum (ER), which is crucial for Sar1's function. By inhibiting ARF, Brefeldin A effectively disrupts the function of Sar1 by halting vesicle transport at an early stage. Similarly, Golgicide A and Exo1 focus on inhibiting the Golgi BFA resistance factor 1 (GBF1) and the Sec7 domain of GBF1, respectively. Both GBF1 and its Sec7 domain are essential for the activation of ARF, critical for COPI vesicle formation. This prevention of ARF activation indirectly affects Sar1, as its role is intertwined with ARF's function in vesicle transport.

Further, inhibitors such as H89 and SecinH3 act on upstream regulators that influence Sar1 activity. H89 impedes protein kinase A, known to phosphorylate proteins that regulate Sar1, thus indirectly decreasing Sar1's activity through reduced regulatory protein function. SecinH3 targets cytohesins, a family of ARF guanine nucleotide exchange factors (GEFs), leading to a reduction in Sar1-related trafficking by impeding ARF-related processes. Conversely, AG1478, MiTMAB, and Dynasore affect Sar1 function by altering processes peripheral to COPI vesicle formation. AG1478, a tyrosine kinase inhibitor, can alter cell signaling pathways that influence vesicle formation, thus indirectly affecting Sar1. MiTMAB and Dynasore disrupt the function of dynamin, a GTPase involved in vesicle scission, which is a step subsequent to the formation of vesicles where Sar1 operates. Finally, ML141, CASIN, Latrunculin B, and Cytochalasin D disrupt the actin cytoskeleton, which plays a role in vesicle transport. ML141 and CASIN inhibit Cdc42, a GTPase involved in actin filament formation, while Latrunculin B and Cytochalasin D prevent actin polymerization and promote depolymerization, respectively. These disruptions to the cytoskeleton can indirectly impact Sar1's role in the transport of vesicles.