In the following, we will highlight in special "user stories" the progress of these projects.
Prof. Ana Garcia Saez, University of Cologne, Institute for Genetics, Germany
Dr. María J. Vicent, Centro Investigación Príncipe Felipe (CIPF), Valencia, Spain
Prof. Dr. Ana Martínez, Center for Biological Research Margarita Salas (CSIC), Spain (planned for 2022-2023)
Prof. Ana Garcia Saez’s project aims to identify small molecule compounds that selectively modulate the dynamics of contact sites between mitochondria and the endoplasmatic reticulum (MERCS). MERCS influence a variety of cellular functions and show altered morphology in several human diseases including neurodegenerative disease and cancer.
The development of new chemical probes, as proposed in this study, could elucidate more mechanistic details about the biological function of MERCS and its role in human pathology. This research could create new opportunities for new pharmaceutical intervention strategies.
The Saez group has recently developed MERLIN: a stable cell line that contains a bioluminescence resonance energy transfer (BRET)-based biosensor that allows the monitoring of changes in MERCS dynamics efficiently with small time and money consumption.1 MERLIN was further optimised to meet the requirements of an automated high-throughput screening campaign (Figure 1).
With this robust assay in place, Prof. Saez was approved for the small molecule screening call in fall 2019. Our EU-OS partner site CIPF led by Dr. María J. Vicent further refined and adapted the conditions from a 96- to a 384-well plate format to enable the screening campaign of the EU-OPENSCREEN European Chemical Biology Library (ECBL). The identified hits were further validated in a dose-response dependent fashion where even one of the molecules showed nM potency with respect to MERCs modulation.
With these hit compounds in hand, Prof. Saez applied for the medicinal chemistry call in autumn 2021 to further improve the performance and therapeutic potential of the identified molecules together with the group of Prof. Ana Martinez at CIB-CSIC.
This follow-up proposal aims to better understand the chemical diversity of the obtained screening hits and to optimise the pharmacological properties of the compounds by designing derivatives with improved ADME (Absorption, Distribution, Metabolism, and Excretion).
A successful outcome of this research will help to discern the mechanism by which these compounds elicit their effect on MERCs. Additionally, it will provide safe compounds with activity at nanomolar concentrations. Altogether, the results produced here could lay the foundation orf a better understanding of MERCS biology and might identify protein components of MERCS as novel drug targets.