Mechanisms of action of emodepside

Abstract

The research of the class of cyclic octadepsipeptides started at the beginning of the 1990s. PF1022A, the starting material of emodepside, is a natural secondary metabolite of the fungus Mycelia sterilia, which belongs to the microflora of the leaves of Camellia japonica. PF1022A consists of four N–methyl–L–leucins, two D–Iactic acids and two D–phenyllactic acids, which build up a cyclic octadepsipeptide with an alternating L–D–L–configuration. Emodepside is a semisynthetic derivative of PF1022A, which contains a morpholine attached in para position at each of both D–phenyllactic acids. Emodepside is efficacious against a variety of gastrointestinal nematodes. Emodepside binds to a presynaptic latrophilin receptor in nematodes. The following presynaptic signal transduction occurs via activation of Gqα protein and phospholipase–Cβ, which leads to mobilization of diacylglycerol (DAG). DAG then activates UNC–13 and synaptobrevin, two proteins which play an important role in presynaptic vesicle–functioning. This finally leads to the release of a currently unidentified transmitter. The transmitter (or modulator) exerts its effects at the postsynaptic membrane and induces a flaccid paralysis of the pharynx and the somatic musculature in nematodes.