Molecular Biophysics and Pharmacology

Finished projects

Metal-based compounds for enhanced cancer immunotherapy

Project ID code: 21-27514S
Provider: GA ČR
Years: 2021 - 2023
Solver: prof. RNDr. Viktor Brabec, DrSc.
The metal-based compounds or their combinations with non-metal-based compounds capable of immunomodulatory activity will be introduced. The results will support the utility of the concept of new anticancer “multi-action” agents that trigger in cancer cells several different events, including synergistic immunomodulatory activities. This concept may open an avenue for developing more potent anticancer chemotherapy with a spectrum of antitumor activity broader than that exhibited by conventional antitumor metal-based drugs already used in the clinic. In this way, these new agents capable of killing tumor cells may offer formulations for future clinical studies to further use in the clinic. Major outcome expected: New anticancer metal-based agents will be proposed, and the associated biochemistry, molecular biology and pharmacology will be developed and examined to formulate theoretical background that will make it possible to propose a novel and more effective drug candidates for further preclinical or clinical examination.

Metallo-supramolecular helicates as DNA condensing agents and carriers for DNA delivery

Project ID code: 20-00735S
Provider: GA ČR
Years: 2020 - 2022
Solver: Mgr. Jaroslav Malina, Ph.D.
This application proposes to explore the ability of metallo-supramolecular helicates to act as carriers for DNA delivery. The dinuclear metallo helicates due to their shape and size offer, compared to the traditionally used cationic metal complexes, unique DNA binding properties and, as we have previously demonstrated, they can compact DNA into nanoparticles and protect DNA molecules from the enzymatic cleavage. We have collected several groups of metallo helicates based on different metal ions [Fe(II), Zn(II), Ni(II), Co(III), Ru(II)] and various multidentate ligands which can bind to DNA and differ in size, shape, charge, spectroscopic properties and stability in biological fluids. All these factors are important to determine their potential as a new type of DNA carriers. We intend to use methods of molecular biophysics to thoroughly explore the DNA binding properties of the helicates as well as the mechanistic details of DNA condensation. Finally, we will explore the efficiency of the helicates to deliver genetic material into cells and compare it with other metal complexes.

Targeting resistance to chemotherapy of tumor cells to reinstate their susceptibility to novel, existing and unsuccessful anticancer metallodrugs

Project ID code: 18-09502S
Provider: GA ČR
Years: 2018 - 2020
Solver: Viktor Brabec
With the intention to better understand the effects, which may play an important role in the biological (pharmacological) action of new combinations of anticancer metallodrugs and agents capable of targeting mechanisms connected with resistance of tumor cells to metallodrugs, new, “dual or multi-action” combinations of chemotherapeutics having the genes that confer resistance to anticancer drugs (cancer resistome) as one of the targets of their action will be introduced and tested. New combinations of metallodrugs and molecules targeting cancer resistomes capable of dual targeting of resistance mechanisms and at the same time DNA will be developed, detailed studies of cytotoxicity, selective targeting into tumor cells, inactivation by coordination to sulfur-containing proteins, DNA binding, cell accumulation, efficiency to affect DNA repair, tolerance of the resulting DNA damage, cellular responses and signaling pathways of new combinations will be performed. To achieve these goals, modern methods of biochemistry, molecular biophysics, oncology and cell pharmacology will be used.

Targeting cancer stem cells by antitumor metallodrugs. Studies on mechanism of action

Project ID code: 17-05302S
Provider: GA ČR
Years: 2017 - 2019
Solver: Jana Kašpárková
With a view to (i) understanding deeply the effects that may play an important role in the biological (pharmacological) properties of the metal-based compounds against cancer stem cells (CSCs) and (ii) developing the next generation of metallodrugs capable of killing the entirety of cancer cells including CSCs, the cytotoxicity, targeting to CSCs and molecular and cellular pharmacology of these compounds will be investigated. The major goal of this project is to explore novel approaches to drug targeting, specifically CSCs. This study is intended to highlight the great, largely unexplored potential of metallodrugs for CSC-directed chemotherapy and to provide hints about the mechanism and targets of systemic toxicity of metallodrugs. Thus, our findings and the urgent medical need for CSC-specific chemotherapies to overcome cancer relapse and metastases formation in the clinic guarantee that the anti-CSC properties of metallodrugs revealed in this study will be pre-clinically and possibly also clinically very appealing.

Translesion DNA synthesis across lesions induced by agents of biological significance. An insight into energetics, kinetics and mechanism

Project ID code: 17-09436S
Provider: GA ČR
Years: 2017 - 2019
Solver: Viktor Brabec
The biological effects of DNA-damaging physical and chemical agents are associated with their ability to affect DNA replication. The main objective of this project is to verify the hypothesis according to which thermodynamic destabilization of DNA due to its damage by DNA-damaging agents is an important factor dictating and controlling the processivity of translesion DNA polymerases. Structurally well-defined DNA lesions derived from the interactions of various agents with DNA characterized by molecular biophysics methods will be used. These are ideal modified DNA model systems for probing correlations between their conformational and thermodynamic properties and processivity of these specific DNA distortions by various eukaryotic translesion DNA polymerases. The long-term goal of this research is to enhance our knowledge of the effects of DNA damaging agents and to use it in the process of prevention of undesirable effects of environmental physical and chemical agents and designing new chemotherapeutics.

Thermodynamics of RNA secondary structures and application to RNA-ligand interactions

Project ID code: 16-03517S
Provider: GA ČR
Years: 2016 - 2018
Solver: Jaroslav Malina
The aim of this research is to employ microcalorimetry to determine more accurate thermodynamic data that are essential for the understanding of RNA structure. Moreover, obtained data will help to clarify the relationship between the thermodynamic stability of the RNA and RNA-ligand interactions.

Mechanistic studies on dual targeting of DNA and histone deacetylase with bifunctional inhibitors

Provider: GA ČR
Years: 2014 - 2016
Solver: Viktor Brabec
With a view to (i) understanding deeply the effects that may play an important role in the biological (pharmacological) properties of the new inert conjugates of histone deacetylase inhibitors with antitumor Pt(IV) complexes [HDACi-Pt}IV)] against cancer cells and (ii) developing the next generation of bifunctional inhibitors capable of dual targeting of histone deacetylase and DNA, the cytotoxicity, selective targeting to cancer cells, DNA binding, cellular accumulation, HDAC inhibitory activity, the cellular response and signaling pathways of the new HDACi-Pt(IV) conjugates will be thoroughly investigated using modern methods of biochemistry, molecular biophysics, oncology and cellular pharmacology. Thus, the major goals of this project are to explore novel approaches to drug targeting and delivery, specifically to the nucleus of the cancer cell and to improve the efficacy of the compounds that have demonstrated ability to kill cancer cells.

Thermodynamics of DNA damaged by physical and chemical agents

Project ID code: P205/11/0856
Provider: GA ČR
Years: 2011 - 2015
Solver: Jaroslav Malina

Metalofarmaka založená na osmiových, platinových a rutheniových komplexech. Od mechanistických studií k nové a efektivnější chemoterapii nádorů.

Project ID code: P301/10/0598
Provider: GA ČR
Years: 2010 - 2014

Protinádorově aktivní komplexy přechodových kovů. Od mechanistických studií k protinádorové chemoterapii.

Project ID code: M200040901
Provider: AV ČR
Years: 2009 - 2013

Izolace a identifikace proteinů z extraktů nádorových buněk, které se váží na DNA modifikovanou protinádorově aktivními metalofarmaky.

Project ID code: P305/10/P143
Provider: GA ČR
Years: 2010 - 2012

Molekulární a strukturní biologie vybraných cytostatik. Od mechanistických studií k chemoterapii rakoviny

Project ID code: GD301/09/H004
Provider: GA ČR
Years: 2009 - 2012

Mechanistické studie mající vztah k cílené chemoterapii rakoviny pomocí komplexů platiny a ruthenia aktivovatelných světlem

Project ID code: IAA400040803
Provider: GA AV
Years: 2008 - 2011

Struktura, rozlišení a zpracování poškození DNA protinádorově účinnými sloučeninami kovů

Project ID code: OC08003
Provider: MŠMT
Years: 2008 - 2011

Komplexy platiny jako agens vhodná pro vytváření můstků mezi DNA a bílkovinami

Project ID code: ME08017
Provider: MŠMT
Years: 2008 - 2010

Nanočásticové a supramolekulární systémy pro cílený transport léčiv

Project ID code: KAN200200651
Provider: AV ČR
Years: 2006 - 2010

Biomolekulární centrum

Project ID code: LC06030
Provider: MŠMT
Years: 2006 - 2010

Metalofarmaka, vývoj a mechanismus působení

Project ID code: 1QS500040581
Provider: AV ČR
Years: 2005 - 2009

Rozlišení DNA modifikované platinovými a rutheniovými cytostatiky proteiny s motivem zinkových prstů a topoisomerázami

Project ID code: KJB400040601
Provider: GA AV
Years: 2006 - 2008

Tolerance poškození DNA protinádorově účinnými komplexy kovů

Project ID code: GA203/06/1239
Provider: GA ČR
Years: 2006 - 2008

Inhibice telomerázy komplexy přechodných kovů. Nová koncepce vývoje nových cytostatik

Project ID code: NR8562
Provider: MZ
Years: 2005 - 2008

Ramanova spektroskopie DNA modifikované protinádorově účinnými komplexy kovů

Project ID code: GA203/05/2032
Provider: GA ČR
Years: 2005 - 2007

Nové přístupy k chemoterapii rakoviny látkami odvozenými od sloučenin kovů

Project ID code: GA305/05/2030
Provider: GA ČR
Years: 2005 - 2007

Strukturní biofyzika makromolekul

Project ID code: GD204/03/H016
Provider: GA ČR
Years: 2003 - 2007

Vnitrobuněčná a mimobuněčná cílová místa protinádorové aktivity a toxicity komplexů ruthenia

Project ID code: 1P05OC070
Provider: MŠMT
Years: 2005 - 2006

Charakterizace metaloproteinů ,klíčových molekul biologických procesů

Project ID code: 1P05OC071
Provider: MŠMT
Years: 2005 - 2006

Strategie pro návrh a syntézu nových léčiv odvozených od kovových sloučenin pro nekovalentní rozlišení DNA

Project ID code: 1P05OC072
Provider: MŠMT
Years: 2005 - 2006

Molekulární mechanismy protinádorového působení nového léčiva BBR3464

Project ID code: KJB5004301
Provider: GA AV
Years: 2003 - 2005

Strategie pro návrh a syntézu nových léčiv odvozených od kovových sloučenin pro nekovalentní rozlišení DNA

Project ID code: OC D20.004
Provider: MŠMT
Years: 2003 - 2005

Vnitrobuněčná a mimobuněčná cílová místa pro protinádorovou aktivitu a toxicitu komplexů ruthenia

Project ID code: OC D20.003
Provider: MŠMT
Years: 2002 - 2005

Charakterizace metaloproteinů, klíčových molekul v biologických procesech

Project ID code: OC D21.001
Provider: MŠMT
Years: 2002 - 2005

Charakterizace metaloproteinů významných v rakovině a jejich interakce s DNA

Project ID code: OC D21.002
Provider: MŠMT
Years: 2002 - 2005

Struktura, rozlišení a biochemie DNA modifikované platinovými cytostatiky

Project ID code: IAA5004101
Provider: GA AV
Years: 2001 - 2005

Biochemie, strukturní a buněčná biologie #netradičních# protinádorově účinných platinových sloučenin

Project ID code: OC D20.001
Provider: MŠMT
Years: 2001 - 2005