Technology Model:

A number of successful drugs are natural products or derivatives of natural products. In contrast to synthetic compounds, natural products are not generated by chemical synthesis but are instead isolated from microorganisms, such as bacteria and fungi. The cyclic peptides constitute an important group of natural product compounds. Drugs such as Penicillin, Vancomycin, Cyclosporin, the Echinocandins, and Bleomycin belong to this group and their successes on the market demonstrate that these types of molecules can be antibiotics and antifungal compounds, as well as immunosuppressive and even cancer drugs.

The structure(s) of a cyclic peptide is usually narrowly defined by the producing organism. Hence, without added modifications, there is only a limited potential for exploration of structural variations that might lead to efficacy improvements or optimization of the compound. Although changes can, and have been made to cyclic peptides (and other natural product compounds), the specific structure(s) and complexity of these molecules require complicated and expensive synthetic chemistries to implement even moderate changes to the structure. Such chemistry efforts greatly reduce the profitability potential of a compound and often results in termination of development. As a consequence thorough explorations, in terms of structural variations, of most cyclic peptide templates are often not feasible. Only a very limited number of these templates have been explored, and typically when a cyclic peptide-based drug candidate requires chemistry, only a small number of derivatives are prepared. Due to these circumstances, the potential of cyclic peptides as drug candidates has not been investigated.

Cyclic peptides are large molecules composed of several biosynthetic units, called amino acids, linked in sequence to form a closed circle (see figure). The producing organisms contain large enzyme complexes, called non-ribosomal peptide synthetase (NRPS) complexes, responsible for the synthesis of these molecules. The NRPS complexes have an assembly line-like organization comprising a number of biosynthetic modules, each of which is responsible for the addition of one, specific amino acid (biosynthetic unit) to the sequence of the cyclic peptide.

Recent progress in understanding the genetics of cyclic peptide biosynthetic (NRPS) complexes has allowed the development of techniques to manipulate the genes encoding these molecules. Consequently, it is now possible to engineer a cyclic peptide- producing organism to synthesize molecules with features that previously had to be introduced by chemistry. More importantly, it is also possible to engineer organisms to produce entirely novel molecules, as single entities, as a defined set, or as combinatorial arrays. Although, the approaches required to produce these organisms are described in recent scientific literature, this concept has to date not been pursued commercially. AureoGen will be first translate these scientific accomplishments into a novel technology with extensive commercial applications.