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A new acetylcholinesterase allosteric site responsible for binding voluminous negatively charged molecules – the role in the mechanism of AChE inhibition

Bondžić, Aleksandra M.; Lazarević-Pašti, Tamara; Leskovac, Andreja; Petrović, Sandra; Čolović, Mirjana B.; Parac-Vogt, Tatjana N.; Janjić, Goran V.

(2020)

TY  - JOUR
AU  - Bondžić, Aleksandra M.
AU  - Lazarević-Pašti, Tamara
AU  - Leskovac, Andreja
AU  - Petrović, Sandra
AU  - Čolović, Mirjana B.
AU  - Parac-Vogt, Tatjana N.
AU  - Janjić, Goran V.
PY  - 2020
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/9028
AB  - Acetylcholinesterase (AChE) inhibitors are important in the treatment of neurodegenerative diseases. Two inhibitors,12-tungstosilicic acid (WSiA) and 12-tungstophosphoric acid (WPA), which have polyoxometalate(POM) type structure, have been shown to inhibit AChE activity in nM concentration. Circular dichroism andtryptophan fluorescence spectroscopy demonstrated that the AChE inhibition was not accompanied by significantchanges in the secondary structure of the enzyme. The molecular docking approach has revealed a newallosteric binding site, termed β-allosteric site (β-AS), which is considered responsible for the inhibition of AChEby POMs. To the best of our knowledge, this is the first study reporting a new allosteric site that is consideredresponsible for AChE inhibition by voluminous and negatively charged molecules such as POMs. The selectedPOMs were further subjected to genotoxicity testing using human peripheral blood cells as a model system. Itwas shown that WSiA and WPA induced a mild cytostatic but not genotoxic effects in human lymphocytes, whichindicates their potential to be used as medicinal drugs. The identification of non-toxic compounds capable ofbinding to an allosteric site that so far has not been considered responsible for enzyme inhibition could befundamental for the development of new drug design strategies and the discovery of more efficient AChEmodulators.
T2  - European Journal of Pharmaceutical Sciences
T1  - A new acetylcholinesterase allosteric site responsible for binding voluminous negatively charged molecules – the role in the mechanism of AChE inhibition
VL  - 151
SP  - 105376
DO  - 10.1016/j.ejps.2020.105376
ER  - 
@article{
author = "Bondžić, Aleksandra M. and Lazarević-Pašti, Tamara and Leskovac, Andreja and Petrović, Sandra and Čolović, Mirjana B. and Parac-Vogt, Tatjana N. and Janjić, Goran V.",
year = "2020",
abstract = "Acetylcholinesterase (AChE) inhibitors are important in the treatment of neurodegenerative diseases. Two inhibitors,12-tungstosilicic acid (WSiA) and 12-tungstophosphoric acid (WPA), which have polyoxometalate(POM) type structure, have been shown to inhibit AChE activity in nM concentration. Circular dichroism andtryptophan fluorescence spectroscopy demonstrated that the AChE inhibition was not accompanied by significantchanges in the secondary structure of the enzyme. The molecular docking approach has revealed a newallosteric binding site, termed β-allosteric site (β-AS), which is considered responsible for the inhibition of AChEby POMs. To the best of our knowledge, this is the first study reporting a new allosteric site that is consideredresponsible for AChE inhibition by voluminous and negatively charged molecules such as POMs. The selectedPOMs were further subjected to genotoxicity testing using human peripheral blood cells as a model system. Itwas shown that WSiA and WPA induced a mild cytostatic but not genotoxic effects in human lymphocytes, whichindicates their potential to be used as medicinal drugs. The identification of non-toxic compounds capable ofbinding to an allosteric site that so far has not been considered responsible for enzyme inhibition could befundamental for the development of new drug design strategies and the discovery of more efficient AChEmodulators.",
journal = "European Journal of Pharmaceutical Sciences",
title = "A new acetylcholinesterase allosteric site responsible for binding voluminous negatively charged molecules – the role in the mechanism of AChE inhibition",
volume = "151",
pages = "105376",
doi = "10.1016/j.ejps.2020.105376"
}
Bondžić, A. M., Lazarević-Pašti, T., Leskovac, A., Petrović, S., Čolović, M. B., Parac-Vogt, T. N.,& Janjić, G. V.. (2020). A new acetylcholinesterase allosteric site responsible for binding voluminous negatively charged molecules – the role in the mechanism of AChE inhibition. in European Journal of Pharmaceutical Sciences, 151, 105376.
https://doi.org/10.1016/j.ejps.2020.105376
Bondžić AM, Lazarević-Pašti T, Leskovac A, Petrović S, Čolović MB, Parac-Vogt TN, Janjić GV. A new acetylcholinesterase allosteric site responsible for binding voluminous negatively charged molecules – the role in the mechanism of AChE inhibition. in European Journal of Pharmaceutical Sciences. 2020;151:105376.
doi:10.1016/j.ejps.2020.105376 .
Bondžić, Aleksandra M., Lazarević-Pašti, Tamara, Leskovac, Andreja, Petrović, Sandra, Čolović, Mirjana B., Parac-Vogt, Tatjana N., Janjić, Goran V., "A new acetylcholinesterase allosteric site responsible for binding voluminous negatively charged molecules – the role in the mechanism of AChE inhibition" in European Journal of Pharmaceutical Sciences, 151 (2020):105376,
https://doi.org/10.1016/j.ejps.2020.105376 . .
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Polyoxometalates in Biomedicine: Update and Overview

Čolović, Mirjana B.; Lacković, Milan; Lalatović, Jovana; Mougharbel, Ali S.; Kortz, Ulrich; Krstić, Danijela Z.

(2020)

TY  - JOUR
AU  - Čolović, Mirjana B.
AU  - Lacković, Milan
AU  - Lalatović, Jovana
AU  - Mougharbel, Ali S.
AU  - Kortz, Ulrich
AU  - Krstić, Danijela Z.
PY  - 2020
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/10139
AB  - Background: Polyoxometalates (POMs) are negatively charged metal-oxo clusters of early transition metal ions in high oxidation states (e.g., WVI, MoVI, VV). POMs are of interest in the fields of catalysis, electronics, magnetic materials and nanotechnology. Moreover, POMs were shown to exhibit biological activities in vitro and in vivo, such as antitumor, antimicrobial, and antidiabetic. Methods: The literature search for this peer-reviewed article was performed using PubMed and Scopus databases with the help of appropriate keywords. Results: This review gives a comprehensive overview of recent studies regarding biological activities of polyoxometalates, and their biomedical applications as promising anti-viral, anti-bacterial, anti-tumor, and anti-diabetic agents. Additionally, their putative mechanisms of action and molecular targets are particularly considered. Conclusion: Although a wide range of biological activities of Polyoxometalates (POMs) has been reported, they are to the best of our knowledge not close to a clinical trial or a final application in the treatment of diabetes or infectious and malignant diseases. Accordingly, further studies should be directed towards determining the mechanism of POM biological actions, which would enable fine-tuning at the molecular level, and consequently efficient action towards biological targets and as low toxicity as possible. Furthermore, biomedical studies should be performed on solution-stable POMs employing physiological conditions and concentrations.
T2  - Current Medicinal Chemistry
T1  - Polyoxometalates in Biomedicine: Update and Overview
VL  - 27
IS  - 3
SP  - 362
EP  - 379
DO  - 10.2174/0929867326666190827153532
ER  - 
@article{
author = "Čolović, Mirjana B. and Lacković, Milan and Lalatović, Jovana and Mougharbel, Ali S. and Kortz, Ulrich and Krstić, Danijela Z.",
year = "2020",
abstract = "Background: Polyoxometalates (POMs) are negatively charged metal-oxo clusters of early transition metal ions in high oxidation states (e.g., WVI, MoVI, VV). POMs are of interest in the fields of catalysis, electronics, magnetic materials and nanotechnology. Moreover, POMs were shown to exhibit biological activities in vitro and in vivo, such as antitumor, antimicrobial, and antidiabetic. Methods: The literature search for this peer-reviewed article was performed using PubMed and Scopus databases with the help of appropriate keywords. Results: This review gives a comprehensive overview of recent studies regarding biological activities of polyoxometalates, and their biomedical applications as promising anti-viral, anti-bacterial, anti-tumor, and anti-diabetic agents. Additionally, their putative mechanisms of action and molecular targets are particularly considered. Conclusion: Although a wide range of biological activities of Polyoxometalates (POMs) has been reported, they are to the best of our knowledge not close to a clinical trial or a final application in the treatment of diabetes or infectious and malignant diseases. Accordingly, further studies should be directed towards determining the mechanism of POM biological actions, which would enable fine-tuning at the molecular level, and consequently efficient action towards biological targets and as low toxicity as possible. Furthermore, biomedical studies should be performed on solution-stable POMs employing physiological conditions and concentrations.",
journal = "Current Medicinal Chemistry",
title = "Polyoxometalates in Biomedicine: Update and Overview",
volume = "27",
number = "3",
pages = "362-379",
doi = "10.2174/0929867326666190827153532"
}
Čolović, M. B., Lacković, M., Lalatović, J., Mougharbel, A. S., Kortz, U.,& Krstić, D. Z.. (2020). Polyoxometalates in Biomedicine: Update and Overview. in Current Medicinal Chemistry, 27(3), 362-379.
https://doi.org/10.2174/0929867326666190827153532
Čolović MB, Lacković M, Lalatović J, Mougharbel AS, Kortz U, Krstić DZ. Polyoxometalates in Biomedicine: Update and Overview. in Current Medicinal Chemistry. 2020;27(3):362-379.
doi:10.2174/0929867326666190827153532 .
Čolović, Mirjana B., Lacković, Milan, Lalatović, Jovana, Mougharbel, Ali S., Kortz, Ulrich, Krstić, Danijela Z., "Polyoxometalates in Biomedicine: Update and Overview" in Current Medicinal Chemistry, 27, no. 3 (2020):362-379,
https://doi.org/10.2174/0929867326666190827153532 . .
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In vivo toxicity evaluation of two polyoxotungstates with potential antidiabetic activity using Wistar rats as a model system

Dinčić, Marko; Čolović, Mirjana B.; Sarić Matutinović, Marija; Ćetković, Mila; Kravić-Stevović, Tamara K.; Mougharbel, Ali S.; Todorović, Jasna; Ignjatović, Svetlana; Radosavljević, Branimir; Milisavljević, Milan; Kortz, Ulrich; Krstić, Danijela Z.

(2020)

TY  - JOUR
AU  - Dinčić, Marko
AU  - Čolović, Mirjana B.
AU  - Sarić Matutinović, Marija
AU  - Ćetković, Mila
AU  - Kravić-Stevović, Tamara K.
AU  - Mougharbel, Ali S.
AU  - Todorović, Jasna
AU  - Ignjatović, Svetlana
AU  - Radosavljević, Branimir
AU  - Milisavljević, Milan
AU  - Kortz, Ulrich
AU  - Krstić, Danijela Z.
PY  - 2020
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/8479
AB  - In this study, thein vivohypoglycemic effect of a donut-shaped polyanion salt (NH4)14[Na@P5W30O110]$31H2O{NaP5W30} and its Ag-containing derivative K14[Ag@P5W30O110]$22H2O$6KCl {AgP5W30}, as wellas their hepatotoxicity and nephrotoxicity, was evaluated. In the screening hypoglycemic study,Wistaralbinorats with streptozotocin induced diabetes were treated intraperitoneally with three single doses (5,10, and 20 mg per kg per b.w.) of both investigated polyoxotungstates. The blood glucose levels,measured before and after 2, 4 and 6 h polyoxotungstate application, showed that both studiedcompounds induced the most pronounced and time dependent glucose lowering effects at the doses of20 mg kg1. Thus, daily doses of 20 mg kg1were administered toWistar albinorats orally for 14 days infurther toxicity examinations. The serum glucose concentration and biochemical parameters of kidneyand liver function, as well as a histopathological analysis of kidney and liver tissues were evaluated 14days after the polyoxotungstate administration. Both investigated compounds did not induce statisticallysignificant alterations of the serum glucose and uric acid concentrations, as well as some of the liverfunction markers (serum alanine and aspartate aminotransferases, and alkaline phosphatase activities).However, the significant decrease in serum total protein and albumin concentrations and the increase inbiochemical parameters of renal function–serum urea (up to 63.1%) and creatinine concentrations (upto 23.3%) were observed for both polyoxotungstates. In addition, the detected biochemical changeswere in accordance with kidney and liver histhopathological analysis. Accordingly, the hepatotoxic andnephrotoxic effects of these potential antidiabetic polyoxotungstates could be considered as mild.
T2  - RSC Advances
T1  - In vivo toxicity evaluation of two polyoxotungstates with potential antidiabetic activity using Wistar rats as a model system
VL  - 10
IS  - 5
SP  - 2846
EP  - 2855
DO  - 10.1039/C9RA09790B
ER  - 
@article{
author = "Dinčić, Marko and Čolović, Mirjana B. and Sarić Matutinović, Marija and Ćetković, Mila and Kravić-Stevović, Tamara K. and Mougharbel, Ali S. and Todorović, Jasna and Ignjatović, Svetlana and Radosavljević, Branimir and Milisavljević, Milan and Kortz, Ulrich and Krstić, Danijela Z.",
year = "2020",
abstract = "In this study, thein vivohypoglycemic effect of a donut-shaped polyanion salt (NH4)14[Na@P5W30O110]$31H2O{NaP5W30} and its Ag-containing derivative K14[Ag@P5W30O110]$22H2O$6KCl {AgP5W30}, as wellas their hepatotoxicity and nephrotoxicity, was evaluated. In the screening hypoglycemic study,Wistaralbinorats with streptozotocin induced diabetes were treated intraperitoneally with three single doses (5,10, and 20 mg per kg per b.w.) of both investigated polyoxotungstates. The blood glucose levels,measured before and after 2, 4 and 6 h polyoxotungstate application, showed that both studiedcompounds induced the most pronounced and time dependent glucose lowering effects at the doses of20 mg kg1. Thus, daily doses of 20 mg kg1were administered toWistar albinorats orally for 14 days infurther toxicity examinations. The serum glucose concentration and biochemical parameters of kidneyand liver function, as well as a histopathological analysis of kidney and liver tissues were evaluated 14days after the polyoxotungstate administration. Both investigated compounds did not induce statisticallysignificant alterations of the serum glucose and uric acid concentrations, as well as some of the liverfunction markers (serum alanine and aspartate aminotransferases, and alkaline phosphatase activities).However, the significant decrease in serum total protein and albumin concentrations and the increase inbiochemical parameters of renal function–serum urea (up to 63.1%) and creatinine concentrations (upto 23.3%) were observed for both polyoxotungstates. In addition, the detected biochemical changeswere in accordance with kidney and liver histhopathological analysis. Accordingly, the hepatotoxic andnephrotoxic effects of these potential antidiabetic polyoxotungstates could be considered as mild.",
journal = "RSC Advances",
title = "In vivo toxicity evaluation of two polyoxotungstates with potential antidiabetic activity using Wistar rats as a model system",
volume = "10",
number = "5",
pages = "2846-2855",
doi = "10.1039/C9RA09790B"
}
Dinčić, M., Čolović, M. B., Sarić Matutinović, M., Ćetković, M., Kravić-Stevović, T. K., Mougharbel, A. S., Todorović, J., Ignjatović, S., Radosavljević, B., Milisavljević, M., Kortz, U.,& Krstić, D. Z.. (2020). In vivo toxicity evaluation of two polyoxotungstates with potential antidiabetic activity using Wistar rats as a model system. in RSC Advances, 10(5), 2846-2855.
https://doi.org/10.1039/C9RA09790B
Dinčić M, Čolović MB, Sarić Matutinović M, Ćetković M, Kravić-Stevović TK, Mougharbel AS, Todorović J, Ignjatović S, Radosavljević B, Milisavljević M, Kortz U, Krstić DZ. In vivo toxicity evaluation of two polyoxotungstates with potential antidiabetic activity using Wistar rats as a model system. in RSC Advances. 2020;10(5):2846-2855.
doi:10.1039/C9RA09790B .
Dinčić, Marko, Čolović, Mirjana B., Sarić Matutinović, Marija, Ćetković, Mila, Kravić-Stevović, Tamara K., Mougharbel, Ali S., Todorović, Jasna, Ignjatović, Svetlana, Radosavljević, Branimir, Milisavljević, Milan, Kortz, Ulrich, Krstić, Danijela Z., "In vivo toxicity evaluation of two polyoxotungstates with potential antidiabetic activity using Wistar rats as a model system" in RSC Advances, 10, no. 5 (2020):2846-2855,
https://doi.org/10.1039/C9RA09790B . .
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