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Synthesis of mono-dithiolene molybdenum complexes and their evaluation as potential drugs for the treatment of human isolated sulfite oxidase deficiency

Objective

Two rare but usually fatal diseases are caused by a failure at different levels of the multistep biosynthetic generation of the three human molybdenum dependent enzymes involved in metabolic processes. In contrast to the more general Moco deficiency (MocoD) affecting all three enzymes, isolated sulfite oxidase deficiency (iSOD) cannot be treated yet. The proposed project is primarily aimed at synthesising a large variety of molybdenum complexes that mimic the natural molybdenum cofactor of the respective enzymes. These compounds will be prepared with a focus on distinct aspects of the biomolecules (first coordination sphere, different functional groups of the complex molybdopterin ligand, hydrogen bonding sites); their stability and ability to catalyse oxygen atom transfer (in particular the oxidation of sulfite) will be assessed and their suitability to bind in the active site pocket of the protein and restore activity will be tested. In addition alternative metals will be investigated with respect to possible benefits regarding stability and activity.
The ultimate aim is to combine all the different synthetic approaches and information about properties to build a compound containing all indispensable functional groups while being stable, active and made with the least possible effort. Consequently this project addresses the human iSOD by developing synthetic structural models for the molybdenum cofactor active site of sulfite oxidase, testing their potential for incorporation into the biotechnologically generated apo-enzyme and evaluating the activity of the resulting semi-synthetic enzymes thereby assessing their suitability as future iSOD treatments. This work will have impact on the way iSOD and MocoD patients will be treated in the future and deepen the understanding of fundamentally important chemical, structural and catalytic aspects of the Moco dependent enzymes.
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Principal Investigator

Carola Schulzke (Prof.)

Host institution

UNIVERSITAET GREIFSWALD

Address

Domstrasse 11
17489 Greifswald

Germany

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 1 402 860,91

Principal Investigator

Carola Schulzke (Prof.)

Administrative Contact

Diana Lode (Ms.)

Beneficiaries (3)

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UNIVERSITAET GREIFSWALD

Germany

EU Contribution

€ 1 402 860,91

UNIVERSITAET POTSDAM

Germany

EU Contribution

€ 48 000

THE PROVOST, FELLOWS, FOUNDATION SCHOLARS & THE OTHER MEMBERS OF BOARD OF THE COLLEGE OF THE HOLY & UNDIVIDED TRINITY OF QUEEN ELIZABETH NEAR DUBLIN

Ireland

EU Contribution

€ 49 009,09

Project information

Grant agreement ID: 281257

Status

Closed project

  • Start date

    1 February 2012

  • End date

    31 January 2018

Funded under:

FP7-IDEAS-ERC

  • Overall budget:

    € 1 499 870

  • EU contribution

    € 1 499 870

Hosted by:

UNIVERSITAET GREIFSWALD

Germany