Hybrid structures based on Amiridine as potential multitarget drugs for Alzheimer's disease treatment
Provider:
Czech Science Foundation
Investigator:
Jan Korabecny, Galina Makhaeva
Abstract:
Amiridine is anticholinesterase drug used in Russia for treatment of Alzheimer´s disease and a number of other neurological disorders. It is an inhibitor of AChE and BChE, it restores fatty acid and phospholipid metabolism, normalizes the physicochemical properties of membranes. However, a search in the scientific databases showed the absence of synthetic work on the preparation of amiridine derivatives. Thus, the task of the project is to create original amiridine–based multitarget molecules with an optimal esterase profile neuroprotective and diseasemodifying properties (antioxidant, anti-glutamatergic and metal-chelating activity, ability to block AChE induced aggregation of beta-amyloid, mitoprotective and microtubulo-stabilizing properties), good BBB permeability, lack of hepatotoxicity and low acute toxicity. We will take advantage of complementary approaches in organic synthesis and in vitro tests of Czech and Russian team, excellence in in silico approaches of Russian team and in vivo experience of the Czech team to reach project objectives and deliver multitargeted ligands.
Project duration:
1-January 2020–31-December 2022
Novel neuroprotective compounds based on NMDA receptor antagonism and cholinergic stimulation
Provider:
Czech Science Foundation
Investigator:
Ondrej Soukup, Martin Horak, Karel Vales
Abstract:
In this project, we would like to follow-up the proof-of-concept project no. 16-08554S, focused on the dually acting tacrine derivatives, in the preclinically-oriented project focused on 7-MEOTA and its derivatives, where we would like to investigate and understand the mechanism of interaction of such compounds with the open-channel of the NMDA receptor. We will use in vitro data of native and specifically mutated NMDA receptors, molecular docking approaches and quantitative structure-activity relationship (QSAR) approach to describe such interaction. Such investigation is giving us also a tool for designing even more effective neuroprotectants. Therefore, the candidates with the most promising pre-clinical potential showing suitable NMDA receptor inhibitory properties while preserving anti-acetylcholinesterase activity will be subjected to thorough preclinical in vivo testing in order to evaluate and verify the real neuroprotective and pro-cognitive value rising from the dual character of such compounds.
Project duration:
1-January 2020–31-December 2022
New approaches to overcome therapeutic resistance of glioblastoma multiforme: Focus on cellular senescence and cerebral organoid model
Provider:
Czech Science Foundation
Investigator:
Zdenek Hodny, Dasa Bohaciakova, Marie Vajrychova
Abstract:
Astrocytoma IV. Glioblastoma multiforme (GBM) is the most serious form of human brain cancer. Over the last 30 years, the median survival of 15 months has not changed. The main cause of this bleak state is the high resistance of GBM cells to current therapies. It is therefore necessary to develop new approaches to the study of GBM biology like developing models that better reflect the relationships between human brain tissue and tumor, using them in studying therapeutic resistance mechanisms and monitoring new drugs effective against GBM. The aim of the project is to create a model of human brain organoid with transplanted GBM (GBM / CO) to study the mechanisms of GBM radio/chemoresistance. Using modern „omic“ analyzes, we want to elucidate the role of therapy-induced cellular senescence in the modulation of GBM cell survival signaling pathways. We also want to identify new compounds with glioblastoma-specific senolytic activity by monitoring chemical libraries and to verify their efficacy in the GBM/CO model.
Project duration:
1-January 2020–31-December 2022
Specific serotonin-dopamin modulators and their potential in the model of induced psychosis
Provider:
Czech Science Foundation
Investigator:
Ondrej Soukup, Jan Korabecny
Abstract:
Current pharmacotherapy of schizophrenia is based on targeted alternations mainly of serotoninergic and dopaminergic system by the second-generation antipsychotics. Besides classic antagonism or partial agoni on dopamine D2receptors, its seems therapeutically beneficial to affect 5-HT3 receptors as well. Current antipsychotics do not show a significant effect on 5-HT3R (with the exception of clozapine), whose antagonization improves, based on research outcomes, sensorial resistance, cognitive impairment, and negative symptoms of schizophrenia. On the basis of augmentation effect of setrons we have therefore proposed and optimized a model (structure) of antipsychotics for animal testing, which could exert partial agonism on D2R, as well as antagonism on 5-HT3R.
We will validate the proposed design in vitro and by the animal model of psychosis also for a tentative clinical use in future. Beside the antipsychotic effect, which should be at ideally comparable to that of clozapine, we believe that the novel model will exert lower incidence of side effects.
Project duration:
1-January 2019–31-December 2021
The influence of experimental gastorintestinal injury and inflammation of pharmacokinetics of Alzheimer´s disease drugs
Provider:
Czech Science Foundation
Investigator:
Jan Bures, Jana Zdarova Karasova
Abstract:
To date there are no information on alteration of pharmacokinetics profile of drugs used in Alzheimer disease (AD) if patients suffer from gastrointestinal dysfunction (due to ischaemia, drug injury and/or inflammatory bowel disease). Such an alteration could be limiting for effective pharmacotherapy of AD. The goal of this project is to determine the significance of capsule enteroscopy to set absorption window of currently available AD drugs and new compound K1065 (a hybrid molecule of tacrine and trolox) in experimental pigs (in health and experimental gastrointestinal injury induced by dextran-sodium sulphate or indomethacin). The second objective is to determine the impact of currently available AD drugs and new compound K1065 on gastric myoelectric activity (as a functional basis for possible gastrointestinal side effects of these drugs). The other aim is in vivo evaluation of pharmacokinetic and anti-inflammatory properties of newly designed compound K1065 in the gastrointestinal tract.
The aim of this project is to set absorption window for pharmacokinetics and bioavailability of currently available AD drugs and new compound K1065 (a hybrid molecule of tacrine and trolox) in experimental pigs and to determine their impact on gastric myoelectric activity.
Project duration:
1-January-2018–31-December-2020
Development of novel radiotrotective agents based on small molecule inhibitors
Provider:
Czech Science Foundation
Investigator:
Jan Marek, Zuzana Sinkorova, Martina Rezacova
Abstract:
Radiotherapy is a very important modality for treating cancer. Its therapeutic potential is however limited by normal tissue damage, which leads to a wide range of symptoms (impeding quality of life of oncologic patients), prevents delivery of intended dose and reduces the tumor-eradicating effect of the therapy. Both acute and chronic radiotoxicity have been associated with cell death. Whereas multiple cell death pathways are executed in cancer cells after irradiation, in radiosensitive tissues such as bone marrow or gastrointestinal tract, the cell death is dominantly mediated via apoptosis. Since a pro-apoptotic protein PUMA plays a key role in this process, its inhibition increases resistance against radiation. Inhibitors of PUMA seem therefore very promising in selective modulation of normal tissue damage durin radiotherapy. Their clinical utilization could be very wide due to PUMA involvement in pathogenesis of myocardial reperfusion injury and neurodegenerative diseases.
Project duration:
1-January-2017–31-December-2019
Novel therapeutic approaches in narcolepsy
Provider:
Czech Science Foundation
Investigator:
Jan Korabecny, Stepan Kubik
Abstract:
Narcolepsy is a condition of orexin deficiency hence, replacement therapy using orexin receptoragonists could be valuable for its treatment. Indications that treatment of narcolepsy with orexinagonists would be effective came from a study demonstrating that chronic overproduction oforexin peptides from an ectopically expressed transgene prevented the development of anarcolepsy syndrome in orexin neuron-ablated mice. Orexin supplementation seemed to be a hopeful way however, a problem with its administration arose as the only effective route is intracerebroventricularly. Therefore, development of small-molecule orexin agonists, able to penetrate BBB, may represent a promising way in treatment of narcolepsy. Additionally, no non-peptide orexin agonist has yet been reported. Pursuant to preliminary screening, 10 potential drug candidates acting as ligands for orexin receptors have been selected. These will be synthesized and in vitro evaluated. The best 4 compounds with desirable biological properties will be forwarded to in vivo studies.
Project duration:
1-January-2017–31-December-2019
Mechanisms of IFNgamma-induced cellular senescence and phenotypic plasticity
Provider:
Czech Science Foundation
Investigator:
Zdenek Hodny, Sona Hubackova, Vojtech Tambor
Abstract:
Senescent cells as non-dividing cells represent a primary tumorigenesis barrier, on the other hand they participate in organism aging and carcinogenesis by production of inflammatory cytokines. Immune system plays a dual role in these processes. Besides clearance of senescent cells from organism it provokes senescence via action of several cytokines. The goal of the study is to highlight molecular mechanisms behind development of senescence induced by interferon gamma (IFNgamma) and transforming growth factor beta (TGFbeta), two cytostatic cytokines principally involved in cancer immune surveillance. We aim to decipher the regulation of key genes involved in growth-suppressing effects of both cytokines, how this control is lost in cancer cells and to characterize phenotypic changes including energy metabolism associated with resistance of these cancer cells to IFNgamma and TGFbeta. We believe this proposal will bring new knowledge about control of cell growth by immune system and mechanisms of escape of tumor cells from immune response mediated by IFNgamma and TGFbeta.
The aim of this project is to characterize cytostatic effects of IFNgamma and TGFbeta with focus on changes in mitochondrial oxidative metabolism and to elucidate phenotypic changes of tumor cells accompanying establishment of resistance to interferon gamma and TGFbeta.
Project duration:
1-January-2017–31-December-2019
Investment evaluation of medical device development
Provider:
Czech Science Foundation
Investigator:
Jan Honegr, Petra Maresova, Martin Augustynek
Abstract:
The aim of the research is to express economic aspects of medical device development. Reasons for solving this problem are limited financial resources of developed countries’ governments, a growing number of patients who live longer due to high quality health care, and governments’ effort to invest in science and research efficiently. The main objective of this project is therefore to create a model capable of describing the potential of investments in medical device development. On its basis it will be possible to optimize processes related to medical device development and market penetration. In order to achieve this objective a review of existing medical device development models will be followed by proposing a new model, which will be discussed with medical device experts from universities, R&D centres, and from companies producing and selling medical devices. The model will be developed for various categories of medical devices. It will lead to creating methodical approaches – supplemented with case studies – to measuring the effectiveness of medical device development.
Project duration:
1-January-2017–31-December-2019
Novel hybrid compounds in the cognitive decline caused by neurodegeneration
Provider:
Czech Science Foundation
Investigator:
Mgr. Martin Horak, Ph.D., PharmDr. Ondrej Soukup, Ph.D., RNDr. Jan Ricny, Ph.D.
Abstract:
This project follows-up with ending 5-year project focused on hybrid compounds. The goal of the project is to characterize predicted NMDA receptor interaction of novel compounds, verified the selected candidate in cognitive decline model in vivo and thus validate the dual approach for such treatment.
Project duration:
1-January-2016–31-December-2018
Plasmonic nanoparticles for theranostics with tunable optothermal properties
Provider:
Czech Science Foundation
Investigator:
prof. Ing. Kamil Kuca, Ph.D., MUDr. Jiri Bartek, CSc., Dr.h.c.
Abstract:
Principal objective is to developed non-toxic gold nanoparticles optothermally tuned "on demand" for specific areas of their application in theranostics and biomedicinal imaging. Surfaces of the gold nanorods and gold nanodumb-bells will be modified with de novo synthesized ligands.
Project duration:
1-January-2016–31-December-2018
Role of oxidative stress in the interplay between cellular senescence and apoptosis
Provider:
Czech Science Foundation
Investigator:
MUDr. Zdeněk Hodný CSc, Mgr. Vojtěch Tambor Ph.D., Mgr. Petra Domašinská
Abstract:
The goal of the project is to unravel the role of oxidative stress in development of cellular senescence and it impact on modulation of interplay between senescence and cell death.
Primarily, cellular senescence (CS) comprises a barrier to cell transformation, however, a persistence of senescent cells in tissues is thought to contribute to augmentation of tumorigenicity of surrounding premalignant cells and to aging and age-related pathologies. A source of these perturbing effects is senescence-associated secretome (SAS) containing inflammatory cytokines. Notably, some species of SAS contribute in autocrine/paracrine way to development of senescent phenotype per se via enhanced activity of oxygen radical-producing systems including NADPH oxidases (Nox). The goal of the proposal is to understand unknown aspects of CS. We aim to decipher a role of the Nox-mediated stress in development of CS in relation to DNA damage, replication stress and to uncover still not fully comprehended and likely complex communication between senescent phenotype and death signaling. We believe this newly gained knowledge will lay down the basis for future efforts to eliminate the senescent cells from organism and to diminish the progress of cancer and aging-associated diseases.
Project duration:
1-January-2015 - 31-December-2017
Provider:
Czech Science Foundation
Investigator:
prof. ing. Kamil Kuča,Ph.D., doc. PharmDr. Daniel Jun, Ph.D., doc. PharmDr. Kamil Musílek, Ph.D., PharmDr. Ondřej Soukup, Ph.D., Mgr. Jan Korábečný, Ph.D., Mgr. Eugenie Nepovimová
Abstract:
The aim of this project is to verify the concept of non-quaternary acetylcholinesterase reactivators as new type of antidotes in case of nerve agent or organophosphorus pesticide poisonings. The goal is to make the decision if this new strategy is a really promising approaach or just blind way.
Acetylcholinesterase (AChE) reactivators based on pyridinium aldoximes (obidoxime, HI-6) are used as causal antidotes in case of nerve agent or pesticide poisonings. Due to the presence of quaternary nitrogen, they have low blood-brain barrier (BBB) permeation and thus they are not capable to fully reactivate AChE in the central nervous system, where nerve agents or pesticides can be responsible for the chronic neural disorders. For this reason, development of novel centrally acting non-quaternary reactivators that can more efficiently cross BBB is one of the most promising strategies. However, from the practical point of view, several drawbacks of physico-chemical, pharmacological and toxicological origin are expected for these non-quaternary antidotes. In this project, all the benefits and negatives of non-quaternary AChE reactivators will be investigated to decide whether this new strategy is a really promising approach or just another blind way in the search for the new type of antidotal therapy.
Project duration:
1-January-2015 - 31-December-2017
Rational design of novel immunomodulators - potential vaccine adjuvans - based on TLR4 ligands
Provider:
Czech Science Foundation
Investigator:
prof. MUDr. Roman Prymula, CSc., Ph.D., Mgr. Jan Honegr, Ph.D., Mgr. Eugenie Nepovimová, RNDr. Dávid Maliňák, Ph.D., Ing. Šárka Salajková
Abstract:
Small-molecule immunomodulators (SMIP) importance lays in the interaction with pathogen recognition receptors (PRR). One of the most important families of PRR is the Toll-like family of receptors. Crystal structure of TLR4, with attached ligand is well described and can be utilized for performing virtual docking. We have identified 60 small molecules with high bonding energy on TLR4 by means of in-silico high-throughput screening of the library containing 10,000 compounds. From these sixty we have chosen 10 compounds which have good potential for synthesis and future modifications. Research will be focused on synthesis of these 10 lead compounds and their testing in-vitro for activity on cell line stably co-expressing human-TLR4. 2×10 derivatives of two best compounds will be synthesized and thoroughly tested for reveal immunomodulation potential using in-vitro, ex-vivo and in-vivo tests.
Project duration:
1-January-2015 - 31-December-2017
