Polytheonamide A/B – Novel biotechnological synthesis of polytheonamide A and B for the use as potent antitumor agents

The polypeptides polytheonamide A and B possess unique cytotoxic properties and are examples for very potent, highly selective and bioactive antitumor agents isolated from the sea sponge Theonella swinhoei. They belong to the largest known class of secondary metabolites. As a consequence of different modifications, the peptides adopt a hydrophobic β-helix that inserts into membranes and forms a minimalistic ion channel, resulting in an extremely high cytotoxicity of picomolar range. The low availability of these metabolites however represents a serious impediment to drug development.

The present invention is based on the isolation of genes responsible for the production of polytheonamide A and B. The so-derived genes could be transferred to easily culturable bacteria to produce the antitumor polypeptides in an ecologically sustainable manner and in theoretically unlimited amounts. Commercial Opportunities: Cancer ranks second in death worldwide and the patient pool for cancer therapies is rising in line with an aging global population. Therefore, the need for optimal therapies is very high. The invention provides means and methods for the reliable and easy production of polytheonamide A and B comprising a polytheonamide A and B gene cluster from previously inaccessible symbiotic producers. Possible strategies for an access to potent antitumor therapeutics open treatment options for malignant diseases. By industrial production, further drug development and clinical studies are possible which enable commercial opportunities in this new area of drugs. In addition, the enzymes modifying the ribosomally encoded polytheonamides provide remarkable potential to biotechnologically engineer peptide libraries in un-precedented ways.

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