H2020Индивидуална стипендия2018–2020

NovInDXS · Development of novel inhibitors of the anti-infective target DXS using dynamic combinatorial chemistry (DCC)

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2018-03-01 → 2020-05-26
Финансиране от ЕС: 171 461 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Нови инхибитори на ензима DXS се разработват чрез динамична комбинаторна химия, за да се блокират процеси, жизненоважни за опасни бактерии, но липсващи при хората. Това помага за създаването на нови лекарства срещу антимикробната резистентност, при която бактериите стават устойчиви на терапиите.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Development of novel inhibitors of the anti-infective target DXS using dynamic combinatorial chemistry (DCC)

Antimicrobial resistance (AMR) is emerging as a serious threat to global public health as bacteria develop new resistance mechanisms and extremely drug-resistant strains are emerging. The current slow speed of drug development and disinvestment of the pharmaceutical industry in the field of anti-infectives is aggravating this problem. In this alarming situation, innovative strategies for drug development and novel targets for which inhibitors with an unprecedented mode of action can be developed are urgently required. NovInDXS aims at the development of selective and potent inhibitors of the important and underexplored anti-infective target 1 deoxy d xylulose-5-phosphate synthase (DXS), an enzyme from the 2C-methyl-d-erythritol 4-phosphate pathway (MEP pathway) that is absent in humans but is essential for medically relevant pathogens. Despite substantial efforts dedicated to the discovery of inhibitors for DXS, to date, very few active compounds have been reported and none of them fulfils the requirements as an ideal candidate for further development. To address these issues NovInDXS used target-directed dynamic combinatorial chemistry (tdDCC) for the identification as well as for the optimisation of new inhibitors of DXS. This new application of tdDCC exhibits a potential of identifying potent hits in less time compared to the traditional medicinal chemistry approach.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

The emergence of multi-drug resistant pathogens is a serious global problem. In this alarming situation, novel targets for which inhibitors with an unprecedented mode of action can be developed are urgently required. This proposal aims at the development of selective and potent inhibitors of the important and underexplored anti-infective target DXS, an enzyme from the 2C-methyl-D-erythritol 4-phosphate pathway that is entirely absent in humans but is essential for medically relevant pathogens (e.g., Plasmodium falciparum, Mycobacterium tuberculosis, Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus). Despite substantial efforts dedicated to the discovery of inhibitors for DXS, to date very few active compounds have been reported and none of them fulfil the requirements as an ideal candidate for further development. To address these issues and maximise the chances of success, we will use dynamic combinatorial chemistry (DCC) as a hit identification strategy for the first time for the enzyme-DXS. To explore hitherto unexplored parts of the chemical space, we will pioneer the use of chiral heterocyclic building blocks in DCC for the discovery of potent inhibitors of the enzyme DXS. Use of chiral heterocycles in DCC will allow to rapidly access novel scaffolds. These chiral heterocyclic scaffolds will be evaluated for their biochemical activity on bacterial DXS. The most promising candidates will be tested in in vivo cell-based assays in bacteria.The proposed approach for the design of chiral heterocyclic inhibitors for novel targets such as the enzyme DXS will enhance the knowledge about this underexplored target and will open up access to various potent inhibitors. Hence, this research programme will greatly improve the chances of idnetifiying new anti-infective agents with a novel mode of action, leading to socio-economical benefits for the health care sector in the European Union and also globally.

Оригинален текст от CORDIS (на английски).

Участници

HELMHOLTZ-ZENTRUM FUR INFEKTIONSFORSCHUNG GMBH · BraunschweigКоординаторГермания