Chemo-enzymatic synthesis of cyclic peptides for highly efficient drug screening processes
Presently, a new research project, dealing with a faster and more efficient process for generating combinatorial libraries, is on its way to get ready for the market. The chemoenzymatic synthesis of pharmacologically highly active cyclic peptides should open new opportunities for drug discovery. Natural cyclic peptides are supreme lead structures for drug development; but their potential has not been fully exploited yet, due to the lack of appropriate technologies. At present, the required tools for generating tailored combinatorial libraries are being developed in a project supervised by IP Bewertungs AG (IPB) and will be soon available on the market.
Cyclic peptides are among the most effective agents to control pathogenic germs, fungal infections as well as for cancer treatment, and hence are of outstanding relevance for drug discovery. Since 1980, two thirds of all newlyapproved drugs were natural products or derivatives thereof. Prominent representatives of cyclic peptide drugs are Daptomycin and Pristinamycin with sales of 450 and 160 million USD in 2008, respectively. Regarding antifungal agents, Echinocandines represent a success story with Caspofungin alone generating sales of 550 million USD in 2008.
In Nature, cyclic peptides are synthesised by various microorganisms. However, their biosynthesis does not occur via the ordinary protein biosynthesis machinery, the ribosome, but rather on large multi-enzyme complexes. Accordingly, this class of substances shows a relatively high structural diversity. Besides the known 20 canonical amino acids, a total of 300 different building blocks, including amino, D-configured and hydroxyl acids, can be used. In the past, this diversity prohibited or at least significantly hampered the synthesis of corresponding natural product derivatives, requiring a time-consuming and costly synthesis and/or tedious retrieval for appropriate drug candidates.
The new innovative process of chemo-enzymatic synthesis involves the synthesis of linear precursor peptides, which are subsequently coupled to reactive leaving groups and finally enzymatically - and hence with highest regio and stereo selectivity - converted to the active cyclic peptide. Given the widely lack of constraints concerning the applied building blocks, implementation of this new technology appears to be highly attractive for commercial purposes.
Proof-of-concept for the successful implementation of this new technology has been already provided by the synthesis and optimization of the natural peptide antibiotic Tyrocidine A. Within a relatively small library of less than 200 compounds, derivatives with considerably improved therapeutic indices (>40fold) could be identified with an extremely high hit rate (>3%, standard procedures in comparison: <0.01%). Given the high potency of the natural lead compounds, this innovative technique can be adopted with comparable efficiency for optimization of the most diverse, cyclic peptide agents.
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