CHAPTER 12: Manufacturing of Venom-Derived Therapeutic Peptides

From the perspective of drug discovery, venoms represent a nearly unlimited and largely untapped source of new biologically active compounds, most of which are of peptidic and proteinic nature. As a result of the progress achieved in recent years in separation and characterization techniques, more and more interesting peptides of venom origin are likely to be identified and further developed into new drugs. A remarkable characteristic of these venom-derived peptide drugs is their large diversity in terms of structure. In this overview, taking advantage of this structural diversity, modern concepts of industrial peptide manufacturing will be presented using the examples of eptifibatide, ziconotide, exenatide and linaclotide. These real world examples will allow discussion of the different synthesis strategies used today in industrial manufacturing processes, including liquid phase peptide synthesis, stepwise solid phase peptide synthesis, and convergent solid phase peptide synthesis. Due to their structural complexity, peptides drugs are generally more expensive to manufacture compared with small-molecule drugs. When a peptide contains non-native amino acid residues or exotic modifications such as cyclic elements, chemical synthesis still remains the only viable route of manufacture. However, and this is another remarkable characteristic of venom-derived peptides, many of them have the necessary stability, potency, and selectivity for therapeutic applications without requiring modifications of their native amino acid sequence. For example, Exenatide and Ziconotide are simply synthetic versions of the native venom peptides without modification. This, in principle, opens up the opportunity for cheaper recombinant production methods, which will not be discussed here.