PEPTIDES & PROTEINS Bachem's headquarters in Bubendorf, Switzerland.
The Melusine Collection is the world’s largest collection of venoms with 1,200 animal venoms in stock. The compounds have been isolated from a wide range of animal types, including snakes, spiders, scorpions, cone snails, sea anemones, jellyfish, bees, wasps, and ants, among others. Melusine libraries ready-made for HTS are comprised of selected venoms that have been pre-fractionated (96- or 384-well microplates). One venom contains from around 200 to a thousand bioactive compounds. Typically each venom provides 80 fractions, each fraction containing from five to ten bioctives. Thus a 96-well plate contains one venom and a 384-well plate contains four venoms. Follow-up steps after obtaining fractions and sub-fractions are the isolation of pure compounds and their validation via synthesis. Key technologies used in the process include mass spectrometry (MS) analysis for primary
evaluation, complete structural elucidation, ie sequencing, and homology searches in databases and bioinformatic loops.
Peptides manufactured at Bachem Bachem is specialised in the process development and manufacture of peptides as active pharmaceutical ingredients (APIs), as well as innovative biochemicals for research purposes. Solid phase peptide synthesis at Bachem is performed with a fully automated synthesizer for small scale-up and in 1,000- litre stainless steel reactors for large-scale production, followed by peptide cleavage from the solid-phase support, thus isolating crude peptide. For large-scale cleavage and separation, the company employs an inverting filter centrifuge in state-of-the-art closed and contained manufacturing systems. Usually the purification is by preparative HPLC and final product isolation is by batch lyophilisation.
Due to steady improvements in chemistry and technology for peptide production, the synthesis of small proteins of up to 100 amino acids is now feasible and therefore chemical manufacturing will be of interest for the production of future peptide drugs. Ligation methods will help to extend the scope of current synthesis and further encourage interest in synthetic proteins. Figure 1 shows the principle of native ligation used in peptide synthesis. Peptide therapeutics manufactured at Bachem include the product MCP-1, as well as Relaxin H2, a member of the insulin superfamily, with the designation H-6784. This is a new compound in the company’s product catalogue and is comprised of a 24-mer A-chain linked to a 29-mer B-chain. Also manufactured by the company is the marketed drug Aprotinin, a 58-mer compound containing three disulfide bonds. The formation of aspartimide is a common side reaction in solid phase peptide synthesis but can be overcome by modifying the synthesis. Another area of intensive investigations relates to the inherent property of peptides of adopting secondary structures, which is a problem for peptide synthesis. Incorporation of pseudo-proline dipeptide units inhibits aggregation phenomena. Pseudo-prolines are now availale in high quality and even large-scale manufacturing has been achieved.
In conclusion
The outlook for therapeutic peptides looks bright due to progress in chemistry, synthesis technology and delivery. The Melusine natural library is ready-made for HTS and represents a major source of new lead compounds. Bachem as a CMO sees complexity as a challenge and the company is working on future technology developments that will constitute a basis for achieving even faster access to interesting structures and for establishing more efficient chemical production of complex drugs in the peptides and proteins field.
Further information Dr Ralph Schoenleber Director Biochemicals & Process Research Bachem AG Hauptstrasse 144 4416 Bubendorf Switzerland
Tel: +41 61 935 2333 Fax: +41 61 935 2325
Atheris squamigera, the green bush viper, is an African snake with a complex venom comprised of enzymes and peptides, including the pHpG enzyme inhibitors. (Photo: R. Stöcklin © Atheris 2011)
22 sp2 November/December 2011
Internet links Email:
ralph.schoenleber@
bachem.com
Web:
www.bachem.com
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