What are peptides

Peptides are naturally occurring biological molecules. Peptides are found in all living organisms and play a key role in all manner of biological activity. Like proteins, peptides are formed (synthesized) naturally from transcription of a sequence of the genetic code, DNA. Transcription is the biological process of copying a specific DNA gene sequence into a messenger molecule, mRNA, which then carries the code for a given peptide or protein. Reading from the mRNA, a chain of amino acids is joined together by peptide bonds to form a single molecule.

There are 20 naturally-occurring amino acids and, like letters into words, they can be combined into an immense variety of different molecules. When a molecule consists of 2-50 amino acids it is called a peptide, whereas a larger chain of > 50 amino acids generally is referred to as a protein.

Peptides are in every cell and tissue in the body

In the human body, peptides are found in every cell and tissue and perform a wide range of essential functions. Maintenance of appropriate concentration and activity levels of peptides is necessary to achieve homeostasis and maintain health.

The function that a peptide carries out is dependent on the types of amino acids involved in the chain and their sequence, as well as the specific shape of the peptide. Peptides often act as hormones and thus constitute biologic messengers carrying information from one tissue through the blood to another. Two common classes of hormones are peptide and steroid hormones. Peptide hormones are produced in glands, and a number of other tissues including the stomach, the intestine and the brain. Examples of peptide hormones are those involved in blood glucose regulation, including insulin, glucagon-like-peptide 1 (GLP-1) and glucagon, and those regulating appetite, including ghrelin.

Peptides need a receptor to penetrate the cells

For a peptide to exert its effect, it needs to bind to a receptor specific for that peptide and which is located in the membrane of relevant cells. A receptor penetrates the cell membrane and consists of an extracellular domain where the peptide binds, and an intracellular domain through which the peptide exerts its function upon binding and activation of the receptor. An example is the GLP-1 receptor, which is located on beta cells in the pancreas. Upon activation of the receptor by natural GLP-1 or a peptide analogue (a synthesized molecule mimicking the effect of natural GLP-1, such as our lixisenatide), the cell is stimulated through a series of biological events to release insulin.


Peptides as drugs

Since peptides play a crucial role in the fundamental physiological and biochemical functions of life, they have for decades now attracted much attention for their potential therapeutic use.

Compared with small chemical entity drugs, peptide based drugs possess certain favorable characteristics, including:

  • Higher potency; peptide based drugs generally are very active on their target receptor, which translates into a high effect at a low dose;
  • Higher selectivity; peptides have a very tight fit to their receptors, which makes them much more selective than smaller molecules. This means that peptides tend to bind only to their target receptor and therefore are less likely to be associated with adverse side effects;
  • Naturally occurring biologics – better safety: Peptides are naturally degraded in the blood stream by circulating enzymes to their component amino acids. As these are natural biological products, peptide drugs are also associated with less accumulation in body tissue and fewer toxicity findings.

Challenges associated with the use of peptides as the basis for therapeutic products:

  • Short-lived: Many natural peptides have a very short half-life; which means that they generally act in the body for only a very short time, 2-30 minutes, before being broken down and the amino acids reused as future building blocks for new peptides.
  • Cannot be administered orally: Most peptides must be administered via injection, because oral administration would lead to degradation and destruction by the digestive system, cleaving the molecules up into separate and therapeutically ineffective amino-acids
  • Low product stability: Many naturally occurring peptides cannot be stored in aqueous solution for more than a few days.

Turning peptides into drugs

It is possible to overcome most of the challenges of using peptides as drugs through peptide enhancement techniques. These aim to constrain the structure of the amino acid chain to make it more rigid and stable, thereby decreasing its susceptibility to degradation, all while maintaining or improving the efficacy of the molecule.

Since its inception in 1998 Zealand has been focused on peptide drug discovery and development and built a world-leading position in the field. We have an experienced and integrated R&D organization, with demonstrated succes in identification of novel biological targets and testing of their therapeutic relevance (idea generation), Innovation, design, modification and optimization of peptides leading to 10 compounds progressing into clinical development.


SIP® Technology

An example of a Zealand proprietary peptide enhancing technology is the SIP® tail technology, which stands for Structure Induced Probe. The SIP® technology adds a number of specific aminoacids to the peptide, thereby strengthening or tightening its molecular structure to make it less susceptible to biological degradation. This ensures a longer life-span in the blood and thereby
permits less frequent dosing. The SIP® technology has been employed for lixisenatide, ZP1846 and elsiglutide.

More recent projects at Zealand have involved the addition of a fatty acid to the amino acid chain of a given peptide as another technique to increase its half life in the blood stream, working with dual acting peptides where one compound is able to simultaneously activate two different peptide receptors (e.g. ZP2929), and the use of new methods to constrain the peptide structure.