PF1022A belongs to a recently identified class of Fig. 1. Structurally, the PF1022 anthelmintics are related to bassianolide, which is an insecticidal metabolite from the fungus Beauveria bassiana (5), and to the enniatins, a class of N-methylated cyclohexadepsipeptides produced by Fusarium species with manifold biological activities (6, 7).Enniatins consist of alternating residues of D-HIV and Nmethylated branched chain amino acids like L-valine or Lisoleucine. Enniatins are synthesized by the multifunctional enzyme ESYN, which was the first N-methyl-cyclopeptide synthetase ever characterized. Biochemical investigations revealed that this enzyme is one single polypeptide chain with a molecular mass of about 350 kDa (8, 9). All catalytic functions necessary for enniatin synthesis, i.e. ATP-dependent substrate activation, thioacylation reactions, N-methylation, and condensation of the covalently bound substrates, are catalyzed by ESYN in a so-called thiotemplate mechanism (10). ESYN represents a hybrid system of a peptide synthetase and a methyltransferase and serves as a model system for other N-methylcyclopeptide synthetases like cyclosporine synthetase (11) and for the peptide synthetase responsible for the synthesis of PF1022 compounds.ESYN catalyzes synthesis of the enniatin molecule from its primary precursors D-HIV and a branched chain amino acid like L-valine or L-isoleucine in an ATP-dependent reaction; the methyl group in the N-methylated peptides is donated by AdoMet. As in other peptide synthetases, 4Јphosphopantethe-ine, covalently attached to the enzyme, acts as a prosthetic group in acylation reactions. Analysis of the ESYN gene (esyn1) of Fusarium scirpi revealed an open reading frame of 9393 base pairs encoding a 347-kDa polypeptide, which contains two highly conserved peptide synthetase domains, EA and EB (9). The EA domain of the protein N-terminal region was identified as the D-HIV binding site. The EB domain of the C-terminal region was identified as the L-amino acid binding site. The EB domain is interrupted by a 434-amino acid insertion responsible for the N-methyltransferase function. An analogous insertion is found in cyclosporine synthetase (9, 12). Both domains (EA and EB) carry a phosphopantetheine prosthetic group.

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The tetra- and mono-thionated cyclic octadepsipeptides represent novel cyclic octadepsipeptide derivatives with broad-spectrum activity against parasitic nematodes in mice and sheep. Some of these show better activity than the potent natural anthelmintic cyclic octadepsipeptide PF1022A against Hymenolepis nana, Heterakis spumosa and Trichinella spiralis larvae in mice. In particular, they show improved efficacy against Haemonchus contortus and Trichostrongylus colubriformis in sheep compared with PF1022A. Here we report on two different and simple synthetic pathways for this new class of thionated cyclic octadepsipeptides.

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