New glutaminyl cyclase inhibitors from marine microalgae and other natural sources as drug candidates for the treatment of periodontitis

• Applicants: Professorin Dr. Carola Griehl; Professor Dr. Stefan Reichert; Professor Dr. Stephan Schilling; Professorin Dr. Susanne Schulz
• Subject Area: Dentistry, Oral Surgery
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 546584339

The aim of the project is the evaluation of substances from marine microalgae and from mosses and liverworts as potential inhibitory pharmaceuticals. Of particular interest are glutaminyl cyclase inhibitory compounds isolated from the lipid fraction of selected marine microalgae species, which belong to classes that have not been studied previously in this respect, i.e. diatoms (Bacillariophyta) and Eustigmatophyceae (Ochrophyta). Cultivation of some of these species is challenging and still being explored, but is crucial as the generation of sufficient algal biomass is a prerequisite for detailed analysis of active compounds and even more for future biotechnological production of algal extracts for phytopharmaceuticals. Glutaminyl cyclases (QC/iso-QC) are current drug targets for the treatment of neurodegenerative and inflammatory disorders, and cancer. A first QC inhibitor PQ912 is currently undergoing a phase 2b clinical study in Alzheimer’s disease. Moreover, QCs have been discovered in pathogenic bacteria of the "red complex", which cause periodontitis. Hence, inhibitors of QC are potential future drugs for treatment of various disorders. The present project focuses on a proof of concept for inhibition of QCs by natural products and their derivatives in models of periodontitis and bacterial infection by periodontal pathogens. Besides algae, mosses and liverworts are to be included in the investigations with regard to QC inhibition and further yet unknown inhibitory mechanisms, as these have shown an inhibitory effect on the periodontal pathogen Porphyromonas gingivalis in preliminary experiments. In previous studies, the applicants demonstrated the inhibition of glutaminyl cyclase by sulfolipid-enriched microalgal extracts in vitro. Yet, studies to proof the efficacy of the new natural QC inhibitors in cellular models and a knowledge for the structural basis of the inhibition for future structure-activity relations studies are still lacking. Therefore, the main objectives of this project are: (I) isolation of sulfolipids and other potential QC inhibitors from natural products and validation of inhibition of human and bacterial QC/iso-QC, (II) verification of the QC/isoQC-inhibition and of the yet unknown inhibitory effect of mosses and liverworts in a cellular model of bacterial growth (P. gingivalis), and (III) in an animal model of periodontitis, (IV) investigation of inhibitor-QC/iso-QC binding complexes, (V) development of drug formulations suitable for the application of hydrophobic actives. Based on the results, lead structure optimization may be performed in future, but also direct exploitation of purified phytoextracts as pharmaceuticals that help to prevent periodontitis.

• DFG Programme: Research Grants