Independent Research Fund Denmark funded four new research projects

Dysregulation of the Ca²⁺/calmodulin-dependent kinase II subtype beta (CaMKIIβ) - a signaling molecule which holds a key function in learning and memory, leads to pathogenesis of several brain disorders, underlying several neuropsychiatric and neurodevelopmental diseases. However, underlaying mechanisms remain poorly understood owing to the lack of isoform-specific molecular tools. Our hypothesis is based on the premise that significant functional differences exist between neuronal CaMKIIβ and α isoforms. To uncover these differences and elucidate currently unknown mechanisms, we aim to identify and validate chemical probes targeting an allosteric binding site unique for CaMKIIb.  The covalent allosteric ligand approach will combine the pharmacological merits of covalent ligands, such as potency and durability of effect, with the additional benefits of the higher specificity of allosteric ligands and, ultimately, open pathways for novel therapeutic strategies in related diseases.

The postdoc employed on the grant will develop the covalent allosteric ligands using a chemistry driven strategy involving computational and organic chemistry, biophysics and structural biology.

Development of a PET tracer for imaging active states of the mGlu2 receptor - A potential new biomarker for schizophrenia

The psychiatric disorder schizophrenia affects around 1% of the population, with severity ranging from manageable to severely disabling. However, severity and type of schizophrenia are determined by assessment of symptoms and patient behavior, rather than specific biomarkers. This impedes our deeper understanding of the disease and thus ability to choose best available treatment option.

Positron Emission Tomography (PET) imaging is a powerful, non-invasive tool for high-resolution quantitative visualization of ligand-receptor interactions. The super-potent and highly selective mGlu2 orthosteric agonist LBG30300 was recently developed in the Bunch research group at University of Copenhagen, and is an excellent starting point for the development of a PET tracer for imaging active states of the mGlu2 receptor. Such insight may provide a ground-breaking understanding of the role of this key receptor in schizophrenia but also depression, Parkinson’s Disease and Alzheimer’s Disease.

While this current project aims at applying the PET tracer in animal studies, ultimately, the new PET tracer will be investigated in healthy humans and patients with schizophrenia, with the aim of disclosing new insight to this disease based on a biomarker.

The project is carried out in collaboration with Tri H.V. Huynh, Associate Professor and Head of Radiochemistry at Herlev University Hospital, and Dr. Philippe Huot at McGill University, Canada. The project is funded by DFF/FSS (project 1) with a Postdoc position.

Computationally de novo designed miniprotein binders enable precise, high-affinity targeting of proteins with known structures. These binders can modulate protein function at user-defined sites with high potency. Despite their promise, most current designs rely on one-shot computational methods without systematic optimization for affinity, efficacy, or stability. Using a recently developed miniprotein binder that potently inhibits acid-sensing ion channel 1a (ASIC1a), this project will establish a robust, generalizable pipeline to enhance binder performance and stability for future mechanistic, therapeutic, and analytical applications.

Using our ASIC1a-targeting de novo designed miniprotein binder as a model, we aim to enhance binder performance and stability through 1) computational diversification using partial diffusion, 2) mRNA display-guided mutational scanning with (non)canonical amino acids and 3) peptide cyclisation via mRNA libraries.

This is a joint grant with the group of Joe Rogers (ILF) and the grant will employ two postdocs: one for the computational diversification and high-throughput screening and one for the mRNA display-guided mutational scanning with (non)canonical amino acids and the peptide cyclisation.

Brain tumors are challenging to treat because medications and radiation cannot easily reach the brain without damaging healthy tissue. This project explores how to safely deliver powerful cancer-targeting radiation to tumors within the brain.

We employ a two-step method for this process. First, an antibody is introduced into the brain, where it attaches to the tumor cells. Next, a small radioactive molecule containing Astatine-211—a radioactive atom—is administered. This molecule binds to the antibody, delivering targeted radiation directly to the cancer cells. This technique is known as pretargeting and has been extensively studied for peripheral tumors, but not for brain tumors.

A postdoctoral researcher will be responsible for the organic synthesis and radiolabeling of small molecules known as tetrazines. They will obtain a library of these compounds and assist in evaluating them both in vitro and in vivo.