CE07 - Chimie moléculaire

Molecular tools for the study of a crucial glycosylated DNA nucleobase in parasites – JADE

Submission summary

In recent years, the application of chemical biology methods for investigating chromatin processes has gained considerable attraction allowing dissecting at the molecular level complex chemical mechanisms enabling chromatin-mediated gene regulation. This project aims to design new chemical tools to gain insight into the biological function of an unusual epigenetic DNA modification, ie a glycosylated nucleobase, called base J, exclusively found in Euglenozoa protiste, more particularly in the Kinetoplastidae pathogenic parasites (such as Trypanosoma and Leishmania transmitted by insect vectors and causing severe infections, often lethal, in humans (Sleeping seekness, Chagas disease, leishmaniasis) and for which our therapeutic arsenal is limited and exhibit toxicity and serious side effects. This epigenetic modification plays a crucial role in the capacity of adaptation and survival of the parasite in its different hosts. Base J biosynthesis pathway is only recently known and constitutes a promising therapeutic target for the development of new medicines against these neglected and (re)emergineg diseases. Up to date, base J biosynthesis pathway was mainly studied by conventional biological approaches and no specific chemical inhibitors have been developed. In this project, we will develop efficient synthetic procedures to obtain new chemical probes and methodologies to characterize this potential therapeutic target. Our objectives are to develop 1) nucleoside analogs inhibiting the Base J metabolic pathway since it is crucial for the survival of Leishmania parasite; 2).a photoaffinity labeling approach using synthetic oligonucletides probes to identify parasite proteins specifically interacting with the nucleobase J; 3) chemical and biochemical tools for studying location, distribution and quantification of base J in a cellular context. This project will bring new therapeutic perspectives in neglected diseases where drugs are lacking.

Project coordination

Dominique Guianvarch (Institut de Chimie Moléculaire et des Matériaux d'Orsay)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

ICMMO Institut de Chimie Moléculaire et des Matériaux d'Orsay
MCAM Molécules de Communication et Adaptation des Microorganismes

Help of the ANR 295,920 euros
Beginning and duration of the scientific project: December 2020 - 36 Months

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