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Infectious diseases

 Antiparasite chemotherapy

The team « Antiparasite chemotherapy » (PARACHEM) is looking for new antiparasite treatments, more specific and less toxic than the present drugs, mainly in the field of leishmaniasis. Leshmaniases are a complex of parasitic diseases provoked by intracellular protozoan of the genus Leishmania, transmitted by an insect vector, the sandfly, and affecting humans and animals. Antileishmanial chemotherapy is expensive, non specific, toxic and drug resistance is usual or at risk. New treatments are necessary on the basis of rational chemotherapy. A first approach consists in identifying and valorizing therapeutic targets with the aim to select drug candidates. A second approach exploits the fact that Leishmania highjacks vesicular trafficking of the host-cell in order to build the parasitophorous vacuole in which it proliferates. Another approach aims to identify new chemical series form natural or synthetic origins through in vitro and in vivo screening on parasite models.
The mechanisms of action of drug candidates are then elucidated as well as their capacity to select drug resistance and the deciphering of associated mechanisms. PARACHEM is also committed in collaborative approaches with the purpose to improve the biodistribution of antiparasite drugs or drug candidates. Moreover, considering the climate warming, PARACHEM is looking for free amoeba, other pathogenic protozoan, which are present in environmental water and tapwater. In parallel of these pathogens survey, PARACHEM has for goal of streamlining anti-amoebal chemotherapy.

The Natural Substances Chemistry team uses its expertise in the synthesis of endoperoxides, via ring expansion reactions and the use of reactive chemical species called peroxycarbenium. In addition, the team has developed a screening method based on mass spectrometry to detect substances with anti-plasmodial activities in the extracts. Moreover, natural substances isolated from different sources available in the team (plants, marine invertebrates, microorganisms, insects, macromycetes) are regularly evaluated against parasites such as P. falciparum, L. infantum, T. brucei.

 Antibacterial and antiviral chemotherapy

The FLUOPEPIT team is developing a research program targeting carbapenemases to fight against antibiotic-resistant Gram-negative bacteria. Multidrug-resistant (MDR) gram-negative pathogens, especially Enterobacteriaceae, are emerging worldwide and are a global public health problem. This is particularly concerning given the current shortage of new compounds active against gram-negative MDRs. β-lactams are among the most frequently prescribed antibiotics to treat bacterial infections. However, their usefulness is threatened by the worldwide proliferation of β-lactamases which have a large hydrolytic capacity, especially in MDR gram-negative bacteria.
The objective is to design and synthesize fluorinated carbapenemase inhibitors with a β-lactam structure. Bulky and hydrophobic fluorinated groups can provide the molecule with better bioavailability. Fluoride is essential in facilitating cell penetration for lactamase inhibition. On the other hand, the very electronegative character of the fluorinated groups can notably modify the properties of the essential functions (carboxyl, amide). In addition, the presence of fluorine improves the pharmacological profile of the molecules and as a probe. Indeed, the laboratory is developing enzyme/ligand interaction studies by 19F NMR.

The Natural Substances Chemistry team is also interested in antibacterial chemotherapies, particularly those associated with β-lactams, due to their allergic prevalence. The team is focused on identifying and designing immunogenic biomimetic peptides for the development of new tools for early diagnosis of drug allergy by targeting memory T cells. In addition, the team also explores unstudied ecosystems to isolate microorganisms and study their production of antibacterial metabolites.

The Biological Chemistry team is interested in anti-infectious chemotherapy by developing non-natural peptides and C-nucleosides.
In the current context, with a growing need for antivirals, the team is developing broad-spectrum C-nucleoside structures. The presence of a carbon bond in a pseudo-anomeric position allows increased stability and opens up opportunities in terms of bioavailability and activity, as demonstrated for Remdesivir. In addition to a pharmacomodulation approach, the team develops prodrugs and vectorization using viral molecular structures.
Thus, we are interested in the fusion peptides of the hepatitis C virus by studying the membranotropic properties with regard to the native sequence modifications related to the peptides ability for structuring in contact with membranes.
The team is also developing fluorinated antimicrobial peptides such as peptaibols and peptides rich in polyprolines. The fluorinated groups make it possible to control both the conformation and the hydrophobicity of the antimicrobial peptides. Fluorinated groups are also used as a probe for studying the interaction of peptides with membranes by 19F NMR.