Towards novel anti-TB drugs
With 1.4 million deaths and 10 million new cases each year, tuberculosis remains a major public health problem. The emergence of antibiotic-resistant strains of the tuberculosis bacillus adds an alarming dimension to this chronic crisis, which is further aggravated by the COVID-19 pandemic. The objectives of the Beam4TB project, coordinated by Hédia Marrakchi (IPBS), are to evaluate the pharmacokinetic properties and toxicity of acetylenic lipids (LACs) whose structures are inspired by those of an anti-infective plant extract, to determine their therapeutic efficacy against tuberculosis, to elucidate their mechanism of action and to identify their targets. This project could lead to the development of new anti-tuberculosis drugs with an original mode of action.
Malaria still kills more than 600,000 people per year worldwide. It is feared that the situation is worsening since resistance to artemisinins (the current main antimalarial drugs) appeared in South-East Asia about 13 years ago. The MAG4 project, coordinated by Dennis Gomez (IPBS) and involving Françoise Benoit-Vical's team (Laboratoire de Chimie de Coordination, Toulouse), aims to explore an original strategy for proposing new antimalarial drugs based on small molecules that specifically target particular DNA structures, the G-quadruplexes, present in the mitochondrial genome of the Plasmodium falciparum parasite.
Macrophage migration in inflammation and cancer
Macrophages are present in all tissues where they ensure homeostasis and immune surveillance. However, when their infiltration is deregulated, they can promote the progression of several pathologies including chronic inflammation and cancer.
Podosomes are adhesion structures of macrophages that allow them to navigate in tissues by degrading the extracellular matrix. The NanoTopoAdhesion project, coordinated by Renaud Poincloux (IPBS), aims to elucidate the molecular mechanisms involved in the ability of podosomes to probe the rigidity of their environment. Based on advanced engineering and imaging techniques, this project could open up original therapeutic perspectives in the context of pathologies where macrophage recruitment is deleterious.
Characterizing and targeting alternative DNA structures
Alternative nucleic acid structures cover all DNA structures that differ from the double helix (known as Watson and Crick). These structures are the subject of intense research efforts to understand where, when and how they form in our cells. Among these structures, three-way DNA junctions are Y-shaped structures whose prevalence in genomes and biological functions are still poorly understood despite their probable association with several diseases, such as Huntington's and Steinert's diseases. The inJUNCTION project aims to develop and use innovative chemical tools to target and study these specific DNA structures. This project involves the team of Sébastien Britton (IPBS) and is coordinated by David Monchaud (Institut de Chimie Moléculaire de l'Université de Bourgogne, Dijon).
Megakaryocytes migration and thrombocytopenia
Thrombocytopenia is a decrease in platelet count that can lead to bleeding, especially in patients treated with chemotherapy. Platelets are produced by megakaryocytes in the bone marrow. A key and still poorly understood step in platelet formation is the passage of megakaryocytes across the vessel barrier (intravasation). The MegaPod project, involving the team of Renaud Poincloux and Christel Verollet (IPBS), and coordinated by Anita Eckly-Michel (Inserm Unit 1255, Strasbourg), aims to study, at the functional and molecular levels, a particular cellular structure, the "PodoPZ", formed by a network of actomyosins organised into interconnected podosomes, and allowing the release of platelets into the bloodstream. This project could pave the way for new treatments for thrombocytopenia.
Inflammasomes and skin disease
Affecting over 3% of adults, psoriasis is one of the most common skin diseases. There is evidence of a genetic predisposition to psoriasis, with polymorphisms in NLRP1 and NLRP3 inflammasome-forming receptors associated with a higher risk of psoriasis. In addition, deregulation of RhoGTPase family enzymes, such as Rac, has also been associated with plaque psoriasis in humans. The PSICOPAK project, involving the team of Etienne Meunier (IPBS) and coordinated by Laurent Boyer (Centre Méditerranéen de Médecine Moléculaire, Nice) aims to elucidate the link between Rac activation, activation of the NLRP1 and NLRP3 inflammasomes by the Pak1 enzyme, a Rac target, and the psoriasis-like inflammatory phenotype. This project could lead to the development of new strategies for the treatment of psoriasis.