Cyclooctadepsipeptides—an anthelmintically active class of compounds exhibiting a novel mode of action

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Abstract

There are three major classes of anthelmintics for veterinary use: the benzimidazoles/prebenzimidazoles, the tetrahydropyrimidines/imidazothiazoles, and the macrocyclic lactones. In nematodes, there are five targets for the existing anthelmintics: the nicotinergic acetylcholine receptor which is the target of tetrahydropyrimidines/imidazothiazoles and indirectly that of the acetylcholineesterase inhibitors; the GABA receptor which is the target of piperazine, the glutamate-gated chloride channel as the target of the macrocyclic lactones, and ß-tubulin as the target of prebenzimidazoles/benzimidazoles. All these anthelmintics are now in serious danger because of the worldwide spread of resistant nematodes in sheep, cattle, horses and pigs. The class of cyclooctadepsipeptides has entered the scene of anthelmintic research in the early 1990s. PF1022A, the first anthelmintically active member, is a natural compound from the fungus Mycelia sterilia that belongs to the microflora of the leaves of the Camellia japonica. PF1022A contains 4 N-Methyl-l-leucines, 2 d-lactic acids and 2-d-phenyllactic acids arranged as a cyclic octadepsipeptide with an alternating l-d-l-configuration. Emodepside is a semisynthetic derivative of PF1022A with a morpholine ring at each of the two d-phenyllactic acids in para position. The anthelmintic activity is directed against gastrointestinal nematodes in chicken, mice, rats, meriones, dogs, cats, sheep, cattle and horses. Moreover, emodepside is active against Trichinella spiralis larvae in muscles, microfilariae and preadult filariae and Dictyocaulus viviparus. PF1022A and emodepside are fully effective against benzimidazole-, levamisole or ivermectin-resistant nematodes in sheep and cattle. In Ascaris suum both cyclooctadepsipeptides lead to paralysis indicating a neuropharmacological action of these compounds. Using a PF1022A-ligand immunoscreening of a cDNA library from Haemonchus contortus a cDNA clone of 3569 base pairs could be identified. This clone codes for a novel 110 kDa heptahelical transmembrane receptor, named HC110R. Database- and phylogenetic analysis reveals that this receptor is a homolog to B0457.1 from Caenorhabditis elegans and has significant similarity to latrophilins from human, cattle and rat. HC110R is located in the plasma membrane and in lysosomes and endosomes. α-Latrotoxin, the poison of the black widow spider, binds at a 54 kDa aminoterminal fragment of HC110R. After binding a Ca2+-influx into HEK293 cells is induced which can be blocked by EGTA, Cd2+ or nifedipin. PF1022A or emodepside also bind to this 54 kDa aminoterminal region of HC110R and interact with the functional responses of α-latrotoxin. In C. elegans antibodies against the C-or N-terminus of HC110R bind to the B0457.1 protein located in the pharynx. Electrophysiological studies reveal that emodepside inhibits pharyngeal pumping of the nematodes in a concentration dependent way with an IC50 value of about 4 nM. Thus, it is tempting to speculate that emodepside exerts its action on nematodes via a latrophilin-like receptor which might have an important regulatory function on pharyngeal pumping.

Introduction

Nematode infections are a major cause of human morbidity and losses of disability adjusted life years (DALYs) in the tropics as well as temperate climate [1]. It is suggested that helminth infections such as that caused by Ascaris lumbricoides, in general, impair the immune response of the host to HIV and tuberculosis by its permanent stimulation in the direction of the TH2 response. It may thus be responsible for the spread of these diseases mainly across Africa and Southeast Asia [2]. In addition, children suffering from Trichuris trichiura infections show a retardation of their cognitive development as well as of growth [3]. In animal health, nematode infections, especially by trichostrongyle species such as Haemonchus contortus, Trichostrongylus spp., Ostertagia spp. etc. play a crucial role mainly in cattle and sheep, leading to enormous economic losses [4]. In addition, companion animals are affected by nematodes. Moreover, some nematode infections of companion animals can afflict man as a zoonosis. For example, Toxocara canis larvae may lead to the toxocariasis in man affecting the brain and eyes [5].

Section snippets

Chemotherapeutic interventions

Since the early 1960s there are three classes of broad-spectrum anthelmintics available. These have been described in detail repeatedly by many authors. A recent overview is given in [6]. Thiabendazole was the first benzimidazole introduced into the market in 1963. Since then a wide variety of other benzimidazoles, benzimidazole carbamates and prebenzimidazoles have been marketed for the control of nematode infections in ruminants, swine, horses, other food animals, in dogs, cats and in humans.

Emerging of resistance

In livestock industry, the situation of anthelmintic treatment has dramatically worsen by the emergence of resistance against all commonly used anthelmintics [4], [9], [10]. Thus, resistance against benzimidazoles is seen in four trichostrongyle spp. of cattle, sheep and goats, and in cyathostomes of horses (Table 1). In some parts of the world, the situation is now so severe that benzimidazoles are not efficient in the treatment of nematode infections in sheep, goats and horses. Against the

Discovery of PF1022A

In 1992, Sasaki et al. reported the isolation and structural determination of PF1022A [11] (Fig. 1), which belongs to the class of the N-methylated 24-membered cyclooctadepsipeptides, consisting of four alternating residues of N-methyl-l-leucine, two residues of d-lactate and two residues of d-phenyllactate. This compound was patented by Meiji Seika Kaisha, LTD (Japan) in 1990 (EP 0 382 173 A2). Since August 1990 there had been close contacts between Meiji Seika Kaisha, LTD and Bayer AG

Total synthesis of PF1022A

There are only very few reports on the total synthesis and structure–activity-relationships of cyclooctadepsipeptides [12], [15], [16], [17], [18]. A report on the biosynthesis of PF1022A and related derivatives has been published recently [19].

A variety of PF1022A derivatives have meanwhile been synthesized; such as modifications and exchanges of the N-methyl leucine residues [20], constrained PF1022A analogues [21], azadepsipeptides [22], thioamide analogues [23] and N-methylated amidoxime

Anthelmintic activity of PF1022A

The anthelmintic activity of PF1022A has been observed in several in vitro and in-vivo studies (Table 2). The first results came from experiments with Ascaridia galli in chicken [28]. It was found that 2 mg/kg was sufficient to exert maximum activity [11]. Against T. canis and Toxocara cati, the intestinal roundworms of dogs and cats, PF1022 A was effective at 0.2 mg/kg given orally [14], [29]. Conder et al. [30] described the anthelmintic profile of this compound in jird against H. contortus,

Anthelmintic activity of emodepside

In 1997, Fujisawa Pharmaceutical Co. Ltd. patented the synthesis of PF1022-221 (emodepside) (WO 97/02256). Emodepside is a semi-synthetic derivative of PF1022A and exerts a high efficacy against a wide variety of nematodes in different animal species (Table 2) [37], [38], [39]. This compound is highly effective against the adult stages of the rat nematodes N. brasiliensis, S. ratti as well as against the mouse nematode H. polygyrus with an oral dosage ranging between 1.0–10 mg/kg. However, its

Electrophysiological studies

The first study in which the neuropharmacological properties of PF1022A, as the first reported member of new anthelmintic 24-membered cyclooctadepsipeptides, have been demonstrated was performed by Terada [14]. Using an in vitro model of A. cantonensis he showed that PF1022A inhibits the motility of the worms. The observed paralysis was partially antagonized by the gabergic antagonists picrotoxin and bicuculline. It can be completely reversed by N-methylcytisine which stimulates the release of

Emodepside action on pharyngeal pumping in C. elegans

Database and phylogenetic analysis revealed 48% identity and 76% similarity of HC110-R with the unknown heptahelical transmembrane 113 kDa protein B0457.1 of C. elegans. Furthermore, sequence data and the dendrogram shown in Fig. 4 indicate the protein B0457.1 of C. elegans to be the homolog to HC110-R. To support this view experiments were conducted by using embryonated C. elegans eggs and preimmunsera directed against the N- or C-terminal regions of HC110-R in order to localize the B0457.1

Outlook

From the present knowledge about the mode of action of this new class of cyclic octadepsipeptides it becomes clear that they possess a very different mode of action from the common anthelmintics (Table 4). Future studies should look for the HC110-R receptor in other nematode species. Furthermore it will be of great importance to find the natural ligand of this latrophilin-like receptor to learn more about its physiological functioning. For this purpose studies using C. elegans are currently

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