Toxicity-Driven Drug Optimization in Novel Antitubercular Agents
Provider:
Czech Science Foundation
Investigator:
Jan Korabecny (University hospital Hradec Kralove), Martin Kratky (Charles University, Faculty of Pharmacy)
Abstract:
The project focuses on safer, more effective antitubercular agents from the template compound K2653 which has shown promise against tuberculosis (TB), however with notable toxicity issues. Facing the escalating challenge of drug-resistant TB, the approach applied in this project encompasses in-depth structure-activity-toxicity relationship analyses for new derivatives to maintain or enhance their efficacy while minimizing the toxicity. A key focus is on modifying toxicity parameters—specifically targeting its cytotoxicity, cardiotoxicity, and biotransformation, to ensure safety without compromising the anti-TB potency. By preparing over 30 designed compounds against resistant mycobacteria, assessing their mechanism of action and in vivo, and foremostly safety profiles, we seek to identify lead candidates that will bring a significant advancement in TB treatment with no cross-resistance to current drugs.
Successful outcomes could significantly impact TB treatment and provide a foundation for a new drug discovery pipeline to be pursued in other fields of drug discovery research.
Project duration:
1-January 2025–31-December 2027
Development of brain organoid models to study the role of cellular senescence in the pathogenesis of glioblastoma
Provider:
Czech Science Foundation
Investigator:
Zdenek Hodny (AS CR), Dasa Bohaciakova (MUNI), Marie Vajrychova (University hospital Hradec Kralove)
Abstract:
N-methyl-D-aspartate receptors (NMDARs) are essential for developing many central nervous system diseases. Although approved blockers acting at NMDARs are available, including memantine and ketamine, a high demand exists for developing compounds acting by a different mechanism. In this project, we will investigate novel potent blockers of GluN1/GluN2 NMDARs based on the structure of K2060 that will (i) exhibit enhanced "membrane-to-channel" inhibition and (ii) exert different inhibition kinetics even in the presence of Mg2+. We will evaluate the inhibitory effect of K2060 derivatives by electrophysiology in HEK293 cells expressing normal (WT) and mutant NMDAR, as well as in hippocampal neurons from WT and "knock-in" (KI; carrying the GluN2A-N615S mutation) mice, in combination with computational approaches (QSAR, docking, and modeling). Finally, using in vivo approaches, we will determine how the observed in vitro parameters affect therapeutic efficacy in modulating audiogenic seizures in the KI mouse model.
Project duration:
1-January 2024–31-December 2026
Novel open-channel blockers of NMDA receptors with enhanced membrane-to-channel inhibition
Provider:
Czech Science Foundation
Investigator:
Ondrej Soukup (University hospital Hradec Kralove), Martin Horak (AS CR)
Abstract:
N-methyl-D-aspartate receptors (NMDARs) are essential for developing many central nervous system diseases. Although approved blockers acting at NMDARs are available, including memantine and ketamine, a high demand exists for developing compounds acting by a different mechanism. In this project, we will investigate novel potent blockers of GluN1/GluN2 NMDARs based on the structure of K2060 that will (i) exhibit enhanced "membrane-to-channel" inhibition and (ii) exert different inhibition kinetics even in the presence of Mg2+. We will evaluate the
inhibitory effect of K2060 derivatives by electrophysiology in HEK293 cells expressing normal (WT) and mutant NMDAR, as well as in hippocampal neurons from WT and "knock-in" (KI; carrying the GluN2A-N615S mutation) mice, in combination with computational approaches (QSAR, docking, and modeling). Finally, using in vivo approaches, we will determine how the observed in vitro parameters affect therapeutic efficacy in modulating audiogenic seizures in the KI mouse model.
Project duration:
1-January 2024–31-December 2026
Biotransformation of tacrine implicating its hepatotoxicity
Provider:
Czech Science Foundation
Investigator:
Ondrej Soukup (University hospital Hradec Kralove)
Abstract:
In this project we would like to explore the toxicity of tacrine which led to its withdrawal from the
market. First, we need to reveal the toxic mechanism of tacrine, i.e., to confirm the current
hypothesis of the toxic pathway 7-OH tacrine- quinone methide – hepatotoxicity. Secondly, we
aim to prove that by a suitable substitution on the tacrine core, we may prevent triggering of the
toxic cascade and develop a compound possessing favorable pharmacological properties while
lacking the toxic ones. We will used human primary spheroides to evaluate the biotransformation of tacrine, and by use of different -species orignating material, we will select the most “man-like” animal model, where our hypothesis will be confirmed. We also believe that by confirming our hypotesis we open a new avenue in the drug design of potential drugs based on tacrine scaffold
avoiding toxic biotransformation and subsequent hepatotoxicity.
Project duration:
1-January 2023–31-December 2025
Structure-activity guided design of novel long-acting antagonists of muscarinic receptors
Provider:
Czech Science Foundation
Investigator:
Jan Jakubik, Jan Korabecny (University hospital Hradec Kralove)
Abstract:
Given the broad range of functions that muscarinic receptors subserve, it is of fundamental importance to find subtype-selective ligands for therapeutic use in specific disorders. Antagonists with long-residence time at receptors are acting longer which allows for a lower daily dose to reach a maximal therapeutic effect. A fundamentally novel class of antagonists are PAM-antagonists that exert positive cooperativity with endogenous neurotransmitter. PAMantagonists preferentially block activated receptors. PAM-antagonists of muscarinic receptors have a therapeutic potential in a selective reversal of persistent excessive agonism under certain pathological conditions, like bronchospasm in asthma. We aim to delineate the molecular mechanisms underlying long-residence time and PAM-antagonism. Based on this knowledge we will design novel long-acting PAM-antagonists.
Project duration:
1-January 2023–31-December 2025
Pnpt1 as a regulator of metabolic reprogramming in phagocytes
Provider:
Czech Science Foundation
Investigator:
Tomas Rousar (University of Pardubice), Ivo Fabrik (University hospital Hradec Kralove)
Abstract:
Excessive activation of tissue resident phagocytes can lead to tissue damage and
autoimmunity. It is known that the pathology is driven mainly by specific phagocyte subtypes
which reprogram their immunometabolism to fuel inflammation. However, the underlying
mechanisms controlling phagocyte metabolic rewiring remain poorly understood. Our data
suggest that the oxidative metabolism in activated phagocytes is regulated by mitochondrial
exoribonuclease Pnpt1. In this project we aim to describe molecular mechanisms and functional
impacts of Pnpt1-dependent regulation of immunometabolism in activated phagocytes in the
context of immune response. To achieve this, we will use modern omics methods, high
resolution respirometry, and functional assays applied to Pnpt1-deficient cells. The obtained
data will provide new insights into the dynamics and control of mitochondrial metabolism in
activated phagocytes.
Project duration:
1-January 2023–31-December 2025
