Technology Research

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 daptomycin, 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. AureoGen’s research focus is on the generation of novel cyclic peptide drug candidates, both through the discovery of new compounds and the modification of existing templates.

NRPS engineering: Until recently, structural modifications of cyclic peptides, for example to convert a native compound into a functional drug, had to be done by complicated and expensive synthetic chemistry approaches. This hampered the development of many promising drug candidates and also prevented optimization (such as reduction of side effects) of some marketed products. Recent advances in the understanding of the biology and genetics of cyclic peptide producing organisms have produced tools and knowledge which allow a wide range of modifications (to a cyclic peptide) to be introduced by altering the sequence of the genes encoding the non-ribosomal peptide synthase (NRPS) complexes responsible for the production of these compounds, in the producer organisms. Engineering of NRPS genes allows for the design of organisms capable of producing cyclic peptides with all the properties required for a finished drug molecule, or molecules requiring only minor chemical modifications. In addition, the technology allows for efficient and cost-effective in-depth exploration of the pharmacological properties of virtually any cyclic peptide template, as well as simple and economical generation of entirely novel cyclic peptides.

Chemo-enzymatic synthesis (CES): The CES technology provides an alternative approach to generating structurally modified cyclic peptides. The technology combines the use of solid-phase peptide synthesis (SPPS), for the synthesis of linear precursor peptides, with a cyclization reaction catalyzed by a recombinant, NRPS gene-derived thioesterase (TE) domain. Recent research has demonstrated that TE domains in (bacterial) NRPS complexes, i.e. the domains responsible for the head-to-tail cyclization of the linear cyclic peptide precursors, can be efficiently expressed, as separate proteins with fully retained activity. It has also been shown that such recombinant TE domains are quite promiscuous and capable of (in vitro) generation of cyclic peptides from a wide range of linear precursors, provided the amino acids at, or close to, the ends of the linear precursors are identical, or similar, to those in the native substrate. This allows for the incorporation of a wide variety of amino acids, as well as other structural elements, into a cylic peptide. It also allows for a considerable variation in the number of residues, in the linear precursor. Thus, the permissive properties of recombinant TE domain enzymes can be exploited for the generation of a wide variety of cyclic peptides and the CES approach has the potential to be used to effectively explore structure activity relationships (SAR) of a cyclic peptide without the need for complicated and costly synthetic chemistry efforts. AureoGen is presently applying the CES technology to generate stable, non-nephrotoxic derivatives of the cyclic peptide drug bacitracin.

Development Program

AureoGen’s drug candidate, AUGC-1, is an antibiotic for the treatment of drug resistant Gram positive infections, in particular meticillin resistant Staphylococcus aureus – MRSA. The compound has successfully completed preclinical development up to the IND-enabling toxicity evaluation and initiation of clinical development. To accelerate the continued development of AUGC-1, AureoGen is actively seeking venture funding for the project.