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Targeting TopoII SIGNED

Mechanistic studies of metal-dependent DNA cleavage in Type II topoisomerase toward therational design of novel anticancer drugs

Total Cost €

0

EC-Contrib. €

0

Partnership

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 Targeting TopoII project word cloud

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Project "Targeting TopoII" data sheet

The following table provides information about the project.

Coordinator
FONDAZIONE ISTITUTO ITALIANO DI TECNOLOGIA 

Organization address
address: VIA MOREGO 30
city: GENOVA
postcode: 16163
website: www.iit.it

contact info
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name: n.a.
surname: n.a.
function: n.a.
email: n.a.
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 Coordinator Country Italy [IT]
 Project website https://sites.google.com/view/jissyak/h2020-project-targeting-topoii
 Total cost 180˙277 €
 EC max contribution 180˙277 € (100%)
 Programme 1. H2020-EU.1.3.2. (Nurturing excellence by means of cross-border and cross-sector mobility)
 Code Call H2020-MSCA-IF-2016
 Funding Scheme MSCA-IF-EF-ST
 Starting year 2017
 Duration (year-month-day) from 2017-11-06   to  2019-11-05

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    FONDAZIONE ISTITUTO ITALIANO DI TECNOLOGIA IT (GENOVA) coordinator 180˙277.00

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 Project objective

Type II topoisomerase (TopoII) metalloenzymes are crucial in regulating DNA topology in replication, transcription, recombination, and repair processes. TopoII is thus a validated target for clinical antibiotics and anticancer drugs. Recent high-resolution X-ray structures of the TopoII/DNA complex showed multiple metal ions bound to the TopoII active site. On the basis of these novel findings, a unified two-metal-ion reaction mechanism for TopoII catalysis has been proposed. However, it is still not clear how this Mg-aided two-metal-ion mechanism permits TopoII to cleave and relegate back DNA strands. Building on our previous studies on metalloenzymes, we seek here to clarify TopoII’s two-metal-aided enzymatic mechanism and identify novel TopoII inhibitors, thus completing the proposer’s computational skill set, boosting her chances of establishing and leading soon an independent computational group. We propose two objectives: First, we will depict the reaction path connecting the enzymatic reactants and products in TopoII. We will achieve this using state-of-the-art computational methodologies such as molecular dynamics (MD) and hybrid quantum mechanics/molecular mechanics (QM/MM) simulations coupled to enhanced sampling techniques for free-energy estimates. We will thus elucidate the metal ion dynamics in TopoII catalysis, together with the metal-induced structural changes that affect the reactivity and efficiency of TopoII catalysis. Importantly, we will investigate TopoII catalysis in the presence of either the catalytic Mg or inhibitory Zn ions in the catalytic pocket. Secondly, we will integrate mechanistic insights on TopoII catalysis with the recent structural and biophysical data on TopoII to decipher drug resistance and identify new TopoII inhibitors. To this end, docking and MD simulations will be used to facilitate the discovery of potent TopoII inhibitors as a first step toward more effective anticancer drugs and new, urgently needed antibiotics.

 Publications

year authors and title journal last update
List of publications.
2018 Alexandria A. Oviatt, Jissy A. Kuriappan, Elirosa Minniti, Kendra R. Vann, Princess Onuorah, Anna Minarini, Marco De Vivo, Neil Osheroff
Polyamine-containing etoposide derivatives as poisons of human type II topoisomerases: Differential effects on topoisomerase IIα and IIβ
published pages: 2961-2968, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2018.07.010
Bioorganic & Medicinal Chemistry Letters 28/17 2020-04-08
2019 Jissy A. Kuriappan, Neil Osheroff, Marco De Vivo
Smoothed Potential MD Simulations for Dissociation Kinetics of Etoposide To Unravel Isoform Specificity in Targeting Human Topoisomerase II
published pages: 4007-4017, ISSN: 1549-9596, DOI: 10.1021/acs.jcim.9b00605
Journal of Chemical Information and Modeling 59/9 2020-04-08

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