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Goran Šinko

Institute for Medical Research and Occupational Health

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Zrinka Kovarik

Institute for Medical Research and Occupational Health

Anita Bosak

Institute for Medical Research and Occupational Health

Vladimir Vinković

Rudjer Boskovic Institute

Nikola Maraković

Institute for Medical Research and Occupational Health

Anamarija Knežević

Rudjer Boskovic Institute

MČ

Maja Čalić

Institute for Medical Research and Occupational Health

Maja Katalinić

Institute for Medical Research and Occupational Health

Vera Simeon-Rudolf

Institute for Medical Research and Occupational Health

Ivana Vinković Vrček

Institute for Medical Research and Occupational Health

Nikolina Maček Hrvat

Institute for Medical Research and Occupational Health

Cooperative Institutions

University of Zagreb

Institute for Medical Research and Occupational Health

Rudjer Boskovic Institute

Greek Rescue Team

Centre National de la Recherche Scientifique

University of California, San Diego

GlaxoSmithKline (Croatia)

Pliva (Croatia)

University of Belgrade

Scripps Research Institute

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Enantioseparation, in vitro testing, and structural characterization of triple-binding reactivators of organophosphate-inhibited cholinesterases

Biochemical Journal (2020)

Nikola Maraković Anamarija Knežević Igor Rončević Xavier Brazzolotto Zrinka Kovarik

The enantiomers of racemic 2-hydroxyimino-N-(azidophenylpropyl)acetamide-derived triple-binding oxime reactivators were separated, and tested for inhibition and reactivation of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibited with tabun (GA), cyclosarin (GF), sarin (GB), and VX. Both enzymes showed the greatest affinity toward the methylimidazole derivative (III) of 2-hydroxyimino-N-(azidophenylpropyl)acetamide (I). The crystal structure was determined for the complex of oxime III within human BChE, confirming that all three binding groups interacted with active site residues. In the case of BChE inhibited by GF, oximes I (kr = 207 M-1 min-1) and III (kr = 213 M-1 min-1) showed better reactivation efficiency than the reference oxime 2-PAM. Finally, the key mechanistic steps in the reactivation of GF-inhibited BChE with oxime III were modeled using the PM7R6 method, stressing the importance of proton transfer from Nε of His438 to Oγ of Ser203 for achieving successful reactivation.

Butyrylcholinesterase

Acetamide

Tabun

Paraoxon

10.1042/bcj20200192

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Citations (17)

Interaction of silver nanoparticles with cholinesterases

Goran Šinko Ivana Vinković Vrček Snežana Miljanić Adriana Dijanošić

The environmental impact of nanomaterials is expected to increase substantially in the near future as they are becoming a part of our daily life. Silver nanoparticles (AgNP) are widely used in the form of cosmetics, food packaging, drug delivery systems, therapeutics, antimicrobial agents, biosensors, or labels. Manufactured nanoparticles can be toxic via interactions with proteins and enzymes. Nanoparticles are known to be able to interfere with cellular metabolism and to cause cytotoxicity and moreover may interfere with specific cellular functions. We studied interaction of AgNP with acetylcholinesterase (AChE) and related butyrylcholinesterase (BChE). Both cholinesterases are present in brain, blood and nervous system. Acetylcholinesterase (AChE) is a key enzyme in cholinergic neurotransmission and inhibition of AChE may lead to fatal outcome. BChE has important pharmacological and toxicological roles due to its hydrolysis of various xenobiotics. We have evaluated the ChE inhibition by AgNPs prepared using reduction methods of silver nitrate with trisodium citrate (AgNP-citrate), hydroxylamine hydrochloride (AgNP-chloride) and sodium borohydride in presence of polyvinyl alcohol (AgNP-PVA). All tested AgNPs inhibited ChEs and the evaluated apparent inhibitor constants ranged from 49 μM to 670 μM. In the case of AChE the inhibition potency increased in the following order: AgNP-PVA < AgNP-citrate < AgNP-chloride, while in the case of BChE the inhibition potency increased in the following order: AgNP-citrate < AgNP-PVA < AgNP-chloride. The impact of AgNP on ChE activity depends greatly on the nature of the nanomaterial coatings. It is also interesting that AgNP showed higher affinity for AChE, than for BChE.

Silver nanoparticle

Butyrylcholinesterase

Trisodium citrate

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Assessment of four organophosphorus pesticides as inhibitors of human acetylcholinesterase and butyrylcholinesterase

Scientific Reports (2021)

Tena Čadež Dora Kolić Goran Šinko Zrinka Kovarik

Toxicity of organophosphorus compounds (OPs) remains a major public health concern due to their widespread use as pesticides and the existence of nerve agents. Their common mechanism of action involves inhibition of enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) which are crucial for neurotransmission. Both chronic and acute poisoning by OPs can leave long-lasting health effects even when the patients are treated with standard medical therapy. Therefore, an increasing urgency exists to find more effective oxime reactivators for compounds which are resistant to reactivation, especially phosphoramidates. Here, we investigated in silico and in vitro interactions and kinetics of inhibition for human cholinesterases with four organophosphate pesticides-ethoprophos, fenamiphos, methamidophos and phosalone. Overall, ethoprophos and fenamiphos displayed higher potency as inhibitors for tested cholinesterases. Our results show that methamidophos-inhibited hAChE was more susceptible to reactivation than hAChE inhibited by fenamiphos by selected oximes. Molecular modelling enabled an evaluation of interactions important for specificity and selectivity of both inhibition and reactivation of cholinesterases. Two newly developed reactivators-bispyridinium triazole oxime 14A and zwitterionic oxime RS194B possess remarkable potential for further development of antidotes directed against pesticides and related phosphoramidate exposures, such as nerve agents tabun or Novichoks.

Butyrylcholinesterase

Methamidophos

Cholinesterase

Pralidoxime

10.1038/s41598-021-00953-9

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To investigate how enzymes work

Priroda (2008)

Goran Šinko

Acetilkolinesteraza je enzim na zlu glasu jer na njega djeluju svi živcani bojni otrovi. No niti je acetilkolinesteraza jedina kolinesteraza niti je svako djelovanje na kolinesteraze stetno. Etopropazin je inhibitor kolinesteraza, ni i lijek protiv Parkinsonove bolesti. Tim se spojem pozabavio dr. sc. Goran Sinko, znanstveni suradniksa zagrebackog Instituta za medicinska istraživanja i medicinu rada, i za svoj rad dobio Godisnju nagradu Drustva sveucilisnih nastavnika i drugih znanstvenika u Zagrebu za mlade znanstvenike i umjetnike za 2007. godinu.

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Oximes: Reactivators of phosphorylated acetylcholinesterase and antidotes in therapy against tabun poisoning

Chemico-Biological Interactions (2008)

Zrinka Kovarik Maja Čalić Goran Šinko Anita Bosak Suzana Berend

Tabun

Pralidoxime

Organophosphate poisoning

10.1016/j.cbi.2008.04.011

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Citations (43)

Alteration of Cholinesterase Activity in Daphnia magna After the Exposure to Silver Nanoparticles

Goran Šinko Ivana Vinković Vrček Lea Ulm Adela Krivohlavek

Daphnia magna

Silver nanoparticle

Cholinesterase

Nanotoxicology

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ENHANCEMENT IN PYRIDINIUM OXIME-ASSISTED REACTIVATION OF TABUN-INHIBITED ACETYLCHOLINESTERASE ACHIEVED BY ACTIVE SITE MUTATIONS

Zrinka Kovarik Maja Katalinić Nikolina Maček Hrvat Goran Šinko Tamara Zorbaz

Tabun

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Preparative HPLC separation of bambuterol enantiomers and stereoselective inhibition of human cholinesterases

Analytical and Bioanalytical Chemistry (2006)

Ivana Gazić Anita Bosak Goran Šinko Vladimir Vinković Zrinka Kovarik

10.1007/s00216-006-0864-9

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Citations (1)

Cholesterol Oxime Olesoxime Assessed as a Potential Ligand of Human Cholinesterases

Biomolecules (2024)

Dora Kolić Goran Šinko Ludovic Jean Mourad Chioua José Dias

Olesoxime, a cholesterol derivative with an oxime group, possesses the ability to cross the blood–brain barrier, and has demonstrated excellent safety and tolerability properties in clinical research. These characteristics indicate it may serve as a centrally active ligand of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), whose disruption of activity with organophosphate compounds (OP) leads to uncontrolled excitation and potentially life-threatening symptoms. To evaluate olesoxime as a binding ligand and reactivator of human AChE and BChE, we conducted in vitro kinetic studies with the active metabolite of insecticide parathion, paraoxon, and the warfare nerve agents sarin, cyclosarin, tabun, and VX. Our results showed that both enzymes possessed a binding affinity for olesoxime in the mid-micromolar range, higher than the antidotes in use (i.e., 2-PAM, HI-6, etc.). While olesoxime showed a weak ability to reactivate AChE, cyclosarin-inhibited BChE was reactivated with an overall reactivation rate constant comparable to that of standard oxime HI-6. Moreover, in combination with the oxime 2-PAM, the reactivation maximum increased by 10–30% for cyclosarin- and sarin-inhibited BChE. Molecular modeling revealed productive interactions between olesoxime and BChE, highlighting olesoxime as a potentially BChE-targeted therapy. Moreover, it might be added to OP poisoning treatment to increase the efficacy of BChE reactivation, and its cholesterol scaffold could provide a basis for the development of novel oxime antidotes.

Butyrylcholinesterase

Paraoxon

Cholinesterase

Tabun

Huperzine A

10.3390/biom14050588

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Enzyme-catalyzed cascade synthesis of hydroxyiminoacetamides

Tetrahedron Letters (2014)

Anamarija Knežević Vladimir Vinković Nikola Maraković Goran Šinko

Candida antarctica

Amide

Cascade reaction

10.1016/j.tetlet.2014.06.027

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Citations (6)