DC8: ANIKA SCHICK (DE)
Partner of attachment: AZ (AstraZeneca AB) SE
Supervisor: Dr. Chad ELMORE
University of Attachment: AU (Aarhus University) DK
Director of Thesis : Prof. Troels SKRYDSTRUP

An approach to track down the journey of a “peptide-drug”
The journey of a drug does not start with the patient taking the medicine. After the molecules invention, the drug needs to undergo safety examinations before it can be made available to the public. In fact, scientists are following the drug’s journey and its fate in living organisms. They need to know when, where and in which state the drug is in the body. But how to track down the molecule under investigation within a body? For this, scientists add a detectable label to the drug, so that they can trace the substance. In this doctoral project we seek to develop a strategy to label “peptide- drugs” with a so-called “radiolabel” such as tritium (3H) or carbon-14 (14C).
Very reliable labels that can be detected at already extremely small amounts are so-called radiolabels. Radiolabels are unstable atoms that differ by mass and excess energy compared to its stable atomic form. Upon decay, radiolabels emit energy. This energy can be made use of by scientists to detect the drug in the body. That’s how a molecules journey within an organism can be followed in an elegant manner. Depending on the drugs (mis)behavior examined with the help of the label the substances fate is determined: either rejection or approval as a drug. For such drug safety studies often one of the two radiolabels 3H or 14C are used in place of the stable atoms 1H and 12C as they are present in the structure of all drugs.
In authorized and specially equipped isotope laboratories, chemists develop routes to incorporate such radiolabels into a drug molecule: In an effective manner, the label should be placed at a position in which the drug can’t lose it. In doing so, as little radioactivity as possible should be used, both due to the radioactive precursors precious existence as well as to minimize radioactive waste. The process of finding an efficient labeling route for each potential drug can often be very time-consuming and cumbersome.
In recent years, peptides (small proteins composed of building blocks called “amino acids”) have become popular as drugs. The humans own biologic machinery produces peptide molecules for many different body functions. Peptide drugs are extremely specific, active at already very low doses, and considered safer. During the safety examination of potential peptide drugs, chemists however lack a reliable method to label these often very big and complex molecules. In this doctoral project, a general radiolabeling strategy for peptide drugs is developed. In our labeling strategy the natural amino acid of the peptide drug is replaced with a unique special amino acid. This building blocks unique moiety can then serve as a “fingerprint” within the key labeling step. The main character – a metal catalyst – comes into play to make the labeling occur: The catalyst is responsible to carry the label, to recognize the fingerprint on the peptide, and to transfer the label onto the peptide. Within few steps the unlabeled peptide with a unique special amino acid can be transformed into a labeled peptide drug with its natural amino acid. As the labeling strategy uses the radioactive precursors carbon monoxide 14CO and hydrogen 3H2 which are toxic, explosive, radioactive and gaseous substances we developed the labeling reaction in a specialized reactor which can be attached to the radioactive source. This allows the chemist to perform the labeling reaction in an efficient and safe manner.
With the described labeling strategy peptide drugs can be labeled with either of the radiolabels 3H or 14C. With this approach we aim to provide an efficient way to label such complex molecules. This will, in the long run, simplify the safety examination procedure of medicines.

Description of illustration: To guarantee the safety of potential new peptide drugs, scientists need to understand when, where and in which state the drug is in the organism. To trace the drug within a human, animal, or cell, the drug needs to bear a label. But how to label a complex peptide drug with a radiolabel? Our approach to put the label onto the drug occurs in a specialized reactor that can be attached to the radioactive gaseous source. In the reactor, a catalyst that carries the radiolabel recognizes the peptide drugs “fingerprint” – a unique special amino acid – and transfers the label to the drug. Herein, the peptide is converted to a labeled peptide with a natural amino acid. This labeled peptide drug helps scientists to uncover the drugs behavior within an organism to guarantee the safety of the drug.