STW grant for HIMS scientists

17. 6. 2013 | Susan

STW has awarded a grant worth € 484.946 to Jan van Maarseveen, Peter Timmerman and Henk Hiemstra for the project entitled “Multicyclic CLIPS-peptides: Next Generation Therapeutic Peptide Drugs” comprising two Ph.D. students and new HPLC equipment.
There is a rapidly growing interest in structurally-constrained peptides that can functionally block the binding interaction between complex proteins, or function as potent inhibitors of enzymes. Multicyclic peptides constitute such a class of compounds.

Novel scaffold molecules
At present, there are hardly any simple synthetic procedures for making these multicyclic peptides. This proposal aims to develop peptide-based multicycles (3- up to 5-rings!!!) using a very simple cyclization procedure. In order to achieve this, we develop a novel family of scaffold molecules that can only form one possible product instead of “polydisperse” isomer mixtures with classical scaffolds earlier developed by us.
Typical scaffolds contain two different types of reactive groups, the reactivities of which do not interfere, and which, consecutively, will react with the corresponding functionality in the peptide.

The novel scaffolds make use of two different “ligation” chemistries. The first reaction (CLIPS: PhCH2Br & peptide-CH2SH) connects the peptide to the scaffold at two positions, while the second reaction (e.g. OXIME: RCH=O + RO-NH2) makes the remaining two connections, ultimately resulting in the formation of a multicyclic peptide.

Peptide libraries
After developing the synthetic methodology, in cooperation with Pepscan (Lelystad, The Netherlands), high-throughput methodology will deliver multicyclic peptide libraries that will be used for screening of model & therapeutic target proteins and, ultimately, the identification of high-affinity inhibitors.