Innovation, Dual Use, and Security: Managing the Risks of Emerging Biological and Chemical Technologies

Chapter 11. Synthesis of Peptide Bioregulators

11 Synthesis of Peptide Bioregulators Ralf Trapp Bioregulators are naturally occurring chemicals that help to ensure the proper functioning of vital physiological systems in living organisms, such as respiration, blood pressure, heart rate, body temperature, consciousness, mood, and the immune response.1 Recent advances in drug delivery have made bioregulators and the chemical analogs derived from them more attractive as potential medicines. Indeed, the growing understanding of these compounds and their functions in the body is likely to bring about profound changes in medicine by increasing the ability to intervene selectively in fundamental biological processes. At the same time, excessive doses of bioregulators can cause severe physiological imbalances, including “heart rhythm disturbances, organ failure, paralysis, coma and death,” giving them a potential for misuse.2 This case study assesses the implications of recent scientific and technological developments involving bioregulators and evaluates governance measures to prevent their application for hostile purposes. Because many bioregulators are peptides, the chapter also examines technologies for synthesizing peptides in industrial quantities. Overview of the Technology Bioregulators modulate the functions of the nervous, endocrine, and immune systems. In terms of chemical structure, they are extremely diverse, ranging from relatively simple molecules in the case of certain hormones or neurotransmitters, to complex macromolecules such as proteins, polypeptides, or nucleic acids. Their physiological action is not limited to any single mechanism, regulatory system, or organ. Malcolm Dando points out that “host homeostatic systems are controlled by midspectrum bioregulators such as hormones and neurotransmitters and the defense system is controlled by the cytokines of the immune system.”3 For example, neurotransmitters such as acetylcholine, norepinephrine, serotonin, or GABA transfer information through the synaptic cleft between neurons, as well 174 R. Trapp as from motor neurons to muscle cells. These messenger chemicals bind to, and interact with, specific receptors on the postsynaptic membrane. Several different neurotransmitters can be released from a single nerve terminal, including neuropeptides . These compounds can act as neurotransmitters in their own right or function as cotransmitters by activating specific pre- or postsynaptic receptors to alter the responsiveness of the neuronal membrane to the action of other neurotransmitters. Further, bioregulators play different physiological roles in various tissues. Indeed, several bioactive peptides in the nervous system were first discovered in the intestine. Additional complexity arises because the nervous, endocrine, and immune systems interact. Modulating the concentration of a bioregulator or interfering with its receptors in one system can affect the function of the other systems.4 Recent research has also provided insights into the role of bioregulator receptors in generating diverse physiological responses and has suggested how they might be manipulated. Because bioregulators maintain equilibrium in body systems, it should be possible, at least in principle, to design molecular analogs that affect body temperature, sleep, and even consciousness in a selective manner. Many bioregulators are peptides, or short chains of amino acids. Examples include angiotensin (which raises blood pressure), vasopressin (which regulates the body’s water balance), Substance P (which transmits pain signals from peripheral receptors to the brain), and bradykinin (which triggers inflammatory responses).5 Minor chemical modifications of peptide bioregulators can create analogs with markedly different physiological properties. The duration of action can also be extended by means of structural modifications that slow its rate of degradation in the body. The understanding of bioregulators has grown at an astonishing pace in recent years, stimulated by new investigation techniques and the interaction of hitherto separate scientific disciplines. Today the functional chemistry of the brain is one of the fastest-growing areas of research in the life sciences.6 A significant part of this progress has been driven by the rapid increase in knowledge about neuropeptides and their receptor and subreceptor systems. Advances in the understanding and use of peptide bioregulators have gone hand in hand with developments in peptide synthesis. Today companies produce peptides to order in quantities ranging from milligrams for laboratory use to hundreds of kilograms for industrial applications. The choice of production method depends largely on the size of the peptide, its amino acid sequence, and the presence of modifications or protective groups. Overall, the chemical synthesis of peptides remains the most common method for industrial-scale production.7 Peptides can be produced in solution (liquid phase) or on the surface of tiny plastic beads (solid phase). One approach involves synthesizing peptide fragments eight to fourteen Synthesis of Peptide Bioregulators 175 amino acids long on a solid-phase resin, removing and purifying...