Ikarugamycin is an antibiotic and a inhibitor of clathrin-mediated endocytosis (CME). Cell surface receptors and their ligands can be internalized by some mechanistically distinct endocytic pathways.
Those signal pathways include clathrin-mediated endocytosis (CME), caveolae-mediated endocytosis (CavME), and caveolae-independent mechanisms (CIE).
There exists a number of pathway to inhibit CME. For example, long-term knockdown or knockout of key components of the endocytic machinery. Additionally, Other methods such as cytosolic acidification cytosolic acidification, hypertonic shock, and potassium depletion. What’s more, some chemical inhibitors play their roles by unknown mechanisms.
More recently, dynamic small molecule inhibitors, such as Dynasore, Dynole-34-2, and Dyngo act as inhibitors of CME. However, these inhibitors exhibit low potency. And some researchers question their specificity and mechanism.
In this article, we will introduce an inhibitor of clathrin-mediated endocytosis (CME), Ikarugamycin.
IKA could inhibit CME in multiple cell lines, including H1299, HCC366 and H1437 cells, ARPE-19 and HBEC3KT. As a result, IKA inhibits TfnR uptake by ~80% in H1299, HCC366, and ARPE-19 cells, and by ~50% in H1437.
TfnR, low-density lipoprotein (LDL) receptor (LDLR), and EGFR all traffic through CME. But they need require different adaptor molecules.
To determine if IKA inhibits CME broadly or is receptor-specific. TfnR, low-density lipoprotein (LDL) receptor (LDLR), and EGFR all traffic through CME. But they need require different adaptor molecules. Treatment with IKA can inhibit CME of each of these receptors.
In conclusion, IKA inhibits selectively inhibits CME over other modes of endocytosis with an IC50 of 2.7 µM. Additionally, this compound disrupts CCP morphology causing a redistribution of AP2 and CHC to the PM.
However, IKA can affect cell viability at high concentration. Nonetheless, because IKA can acutely and reversibly inhibit CME selectively. This compound is also a useful tool under specific conditions to inhibit CME.
Elkin SR, et al. 2016 Oct;17(10):1139-49.