Peptides are organic compounds made up of natural amino acids in living organisms. Originally isolated from biological sources, they are synthesized chemically today. The biological properties of peptides depend on the number of amino acids involved and their position in the amino acid chain. The 20 natural amino acids are enough to form the basis for an unimaginably large number of peptides, each with their own distinctive physical, chemical and biological properties.

Peptides are mainly used as highly active and highly specific drug substances. Oncology and diabetes/obesity are prominent examples of therapeutic areas in which peptides generate billions of dollars in revenues.

Naturally occurring peptides like the hormones insulin and glucagon are highly active even in small amounts. These hormones are released systematically in the body, take effect rapidly and are broken down by the organism within minutes in many cases. Many biochemical processes are controlled by sophisticated feedback loops of this kind with the aid of peptides. In contrast, the active pharmaceutical ingredients used for therapeutic purposes, primarily in the management of chronic disease, generally have longer durations of action, enabling extension of the dosing intervals to days or weeks.

One strategy used with great success in nature to extend the lifespan and hence the activity of peptides in the organism is cyclization. In this process, an additional chemical bond – for instance between the two ends of a linear peptide or the side chains of two amino acids – results in the formation of molecules with a ring structure. Also known as macrocycles, such compounds are more resistant to enzymatic breakdown than their open-chain counterparts and bind to their biological target with an even higher degree of affinity and selectivity. Some macrocycles produced from fungi and bacteria – examples being cephalosporins and erythromycin – are well-established and essential antibiotics. The use of orally available cyclosporine A since the 1970s to suppress natural immunity has revolutionized organ transplantation medicine.

Researchers learning from nature are increasing their efforts to use peptides with a ring structure to reach bonding sites that existing drugs have been unable to target. Unlike conventional small organic compounds, macrocycles are ideal due to their size for modulating protein-protein interactions (PPIs) involving extensive binding surfaces. Inhibition of PPIs is being investigated in a number of clinical trials, including trials to develop cancer treatments, and the first such medicines have already been granted marketing authorization.

New scientific insights are helping us to understand why some macrocycles are absorbed better than others into the bloodstream after oral use or are better able to penetrate cell membranes. This knowledge enables the design of new macromolecules with tailored properties. With the advances in chemical peptide synthesis accomplished in recent years, Bachem is now able to develop efficient manufacturing processes for complex cyclic peptides. In providing these agents, Bachem is making a significant contribution to the further clinical research and exploitation of this promising drug class.

The glycosylation technology permits the synthesis of peptides and proteins with pre-attached sugars, selected from a proprietary library of over 50 specific glycans. It has been shown to markedly improve drug properties such as half-life, binding affinity and selectivity. Furthermore, compared to recombinant products, the chemically synthesized proteins are more homogeneous. Glycosylation of peptide drugs can be a powerful way to enable optimization of lead candidates. Selective, site-specific glycosylation leads to a homogeneous product with potential for more defined bioactivity compared to heterogeneous products.

Bachem Holding AG and GlyTech, Inc. were 2013 CPhI innovation prize finalists for the groundbreaking work on Interferon Beta-1a. The technology has been used in multiple other projects, such as to manufacture glycosylated somatostatin analogues and glycosylated GLP-1. In all cases, drug improvements were achieved.

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