Malaria is one of the most widespread parasitic infections in the world, infecting more than 300 to 500 million people and is responsible for the death of 1 million people a year. The spreading of Plasmodium falciparum infection is due to the emergence of resistance to almost all available antimalarial drugs. Concerned by the need to produce cheap and easy-made drugs, most researchs devoted to find new antimalarial agents are restricted to improving existing drugs, even if their therapeutic potential can be endangered by existing resistances to the biological target(s). Within this context, our project goal is to develop a new and promising therapeutic agent with a new chemical scaffold and having an unprecedented pharmacophoric function (Spiro-Cyclohexadienone) for treating malaria, with the expectation that new mode of action(s) can be identified at the end. Two important families of antimalarial agents, the quinine and the artemisinin, were isolated from plants, selected along human history (traditional pharmacopoeia) for their virtue to treat fevers. Inspired by this approach, a potent new class of antimalarial natural products, the aculeatins, were identified in 2000 from a plant used in traditional phytotherapy in Papoua-New-Guinea to treat fevers. A few years ago, we have demonstrated that a highly efficient cascade reaction, enable to make multiple bonds formations via a biomimetic mechanism can ends up by forming the complex polyspirocycles structure of aculeatins, starting just from a simple phenol and a carbonyl groups. By mastering this biomimetic protocol, we were able to make quickly and simply the set of structurally complex molecules having the essential features of antiparasitic agents, given important insights on the structure/activity relationship. We are working on the development of molecules having many advantageous points: i) an in vitro efficiency against P. falciparum at nanomolar concentration and with a selectivity index over 100 (efficiency on the parasite compared to the cytotoxicity on human erythroblaste), with a remarkably fast action, ii) a potency on the parasite at every blood stages and iii) a dual pharmacophoric group which amplify the biological effect. During the 24 month of this project, we propose to extent the proof-of-concept with the objectives to enhance the in vitro activity by one order of magnitude (the low nanomolar range) and to be able to cure malaria at blood stage in a rodent model. The goal is to bring a new drug candidate at the drug development stage concerning its pharmacological profile and efficiency. This drug candidate can be further launched into regulatory preclinical trials that would include detailed toxicological studies in association with pharmaceutical groups (licence transfer).

A tremendous effort is currently being undertaken by the scientific community to develop drug delivery systems in which the release of the active substance is controlled “on demand”. The key-issue is to control the physical and chemical properties of the drug encapsulated in the delivery system as they directly affect the way the material is formulated and presented to the consumer and influence more fundamental features such as its solubility and dissolution rate. These factors, as well as the considerable financial gains to be realized by effective patent protection of new drug physical forms, have resulted in a flurry of activity in screening for novel solid forms, including salts, polymorphs, co-crystals. Mesoporous materials such as templated silicas or Metal Organic Framework (MOF) appear as potential drug delivery systems due to their interesting properties such as their uniform porous structure, high surface area, tunable pore sizes with narrow distribution and good biocompatibility. Up to now, drugs were physically adsorbed into the channels or cages of the mesoporous materials. Unfortunately, this loading method requires several steps to achieve the final drug loaded and functionalized materials. Moreover, the organic solvents have to be carefully chosen as they could affect the drug solubility, the drug/silica surface interactions, and, as a consequence, the loading and release behavior of the material. The aim of the present research project is to design a new route to the encapsulation and delivery of drugs based on materials called ionogels obtained by the confinement of ionic liquids in silica matrices by means of sol-gel synthesis. The use of ionogels will allow 1) increasing the solubility and 2) controlling the release of the drug. Moreover, they can be cast in different shapes which is a key-advantage as it makes the final pharmaceutical form process much simpler. In this research project, we propose to replace a component of the ionic liquid by the drug or active substance (such as ibuprofen) in order to obtain new tunable drug delivery systems. The main advantage of using ionogels is that the drug-based ionic liquid, which is the structuring agent, is firmly maintained inside the material: the ionic liquid has a dual role of structuring agent and drug. The synthesis is a one step process, in contrast to the loading method in classical mesoporous materials which is time and solvent consuming. The use of drug based ionic liquids will allow increasing considerably the solubility of the drug. Finally, the confinement in the silica matrix will allow controlling the relase of the drug by playing with the physical and chemical properties of the delivery system (guest/surface interaction, pore diameter, etc.). Our objective is to synthesize such drug-based ionogels and understand using both experimental and molecular simulation approaches the crucial parameters that control their physical and chemical properties. In particular, the key factor that has to be understood and controlled is the subtle balance between the structural stability and dynamics of the drug-based ionogels. On the one hand, the material has to show good mechanical stability in order to be considered as a promising candidate for the design of new pharmaceutical products (to take advantage of the different casting processes offered by ionogels). On the other hand, the dynamics of the confined substances has to remain fast enough to allow release of the drug in a simple, efficient, and controlled manner.

The classification of the influenza viruses of A type rests on antigenic specificities of both main surface glycoproteins: Hemagglutinin (HA) and Neuraminidase (NA). Interaction between sialic acid residues of cellular membrane and HA lectin of influenza viruses is the first step of infection allowing then the entry of the viral genome into the target cells. The NA plays a part in the final stage of the viral cycle by hydrolyzing the connections HA-sialic acid thus allowing the release of the neo-synthesized viral particles. There are only two antiviral molecules directed against NA: oseltamivir and zanamivir (Tamiflu® and Relenza®) but some resistance already appeared. So far, there is no medical drug to prevent the viral entry. We believe that understanding the relationship of sialic acid/HA interactions will open new therapeutic pathways. The aim of this project is to develop a high-throughput technology for the screening of sugar/HA interactions determining the optimal multivalent structure of the saccharides for the binding to influenza virus. Natural oligosaccharides are enormously diverse and their chemical as well as enzymatic synthesis is not trivial for commonly studying their interactions. Recently reported glycoarrays permit it on small scales. However, oligosaccharide synthesis still remains complex and glycoarrays must be improved especially to detect sugar/lectin weak interactions. Particularly, direct immobilisation onto the surface array may somewhat interfer with an optimal availability to the lectin. Furthermore, close contact of the surface array could also interfere with the sugar/lectin interaction. To overcome these problems, we propose in this project to synthesise conjugates constituted of a glycomimic linked to an oligonucleotide label and to use DNA chips as an addressing tool. Several glycomimics in which saccharidic units are linked together through a non saccharidic backbone such as small peptides, cyclodextrines or polymers have been reported. The novelty of our glycomimics and of their conjugates with oligonucleotides is that their syntheses are performed within hours on solid support using the combined efficiencies of the DNA synthesis and of the Click chemistry. Starting from oligonucleotide bearing a network of alcyne functions and from simple azido saccharide units, such simple methodology easily permits to generate a great variety of mimics differing from the number and distance between sugars, but also with different hydrophilicity/hydrophobicity balance and with various backbone structures in order to find the best glycomimic for a given lectin. Thus, a simple method will allow to generate a great diversity of structures. Preliminary results have shown the potential of this synthetic approach and of the consequent use of the conjugates on DNA chips for lectin interactions. Glycomimic-DNA conjugates with one to three identical sugars separated by a rigid or flexible linker have been used according to two different ways: either the hybridisation of the conjugate to the oligonucleotide bound to the array surface was followed by the lectin recognition, or the recognition in solution of the conjugate with the lectin was followed by the immobilisation of the complex to the array surface by hybridisation of the oligonucleotide label. Detection of the recognition by fluorescence has shown that both approaches worked with one of the lowest detection limit of reported glycoarrays (2-20 nM of lectin) and moreover without consuming a large amount of the DNA-glycomimetic (1M). (J. Org. Chem. 2006, Angew. Chem. 2007) This multidisciplinary project will be developed by a consortium of 4 complementary partners who are respectively specialist in saccharides, oligonucleotides and their conjugates, DNA chips and influenza viruses. The aim of this project is the design and the development of an efficient tool for the rapid study of carbohydrate/HA interactions in order to 1) discover new glycomimic ligands of HA blocking their activity, 2) rapidly diagnose the infection by influenza viruses in the population at risk and 3) distinguish the human and avian influenza viruses.

The synthesis of nucleic acids in living organisms is very precisely controlled. This remarkable fidelity in information transfer is the result of selective polymerization and correction enzymes. In the absence of these enzymes, chemically-controlled DNA synthesis is by contrast poorly efficient and less selective. In this context, the structuring of bio-inspired artificial genetic systems is a field of growing importance. The objective of this approach is to decompose a complex phenomena of life (DNA synthesis) into a set of simple phenomenon with complementary functions themselves interacted. One approach to achieve this goal is the template-directed formation of internucleosidic linkages in the absence of enzymatic or chemical activation. These chemical systems need to provide elements of molecular recognition as well as proof-reading control and reversible covalent bonds are well fitted for this task as they can lead to new materials able to repair themselves or transform in response to their environment. Among the many reversible covalent reactions, boronate esters that are formed dynamically by the reaction of a boronic acid and a cis-diol have not been exploited so far in the nucleic acid field. Usually designed and evaluated as probes for sugar detection, boronic acids can bind 1,2- or 1,3-cis-diol-containing molecules through the reversible formation of 5 or 6-membered cyclic boronate esters without chemical activation. In the presence of water, there is an equilibrium between free boronic acids and boronate esters depending on various parameters: substitution of the diol moiety, substitution of the boronic acid, pH and temperature of the medium, presence of anions, etc… Thus, boronate esters are able to reversibly dissociate and associate and rearrange their molecular components depending on the media. Moreover, boron chemistry seems to have played an important role on early earth as borate minerals was presumably involved in the prebiotic synthesis of ribose. We recently described the completion of the set of four 2’-deoxy-5’-borononucleotide analogues of natural nucleotide monophosphates. Our goal is to develop a new type of boronic acid-based internucleosidic linkage. Indeed, the boronic acid-diol equilibrium is directional and its reversibility allows the formation of thermodynamically stable architectures. Thus, the incorporation of these analogues into DNA strands and the study of their binding abilities will help our understanding of the encoding of genetic information. Such system might allow the template-directed self-assembly of boronic acid building blocks without chemical activation and should also be the first step towards the conception of an artificial self-replicating genetic code. Controlling the formation of such systems could be relevant for the design of dynamic “smart” nucleic acids-based polymers. The goal of the present application is the creation of an artificial genetic system based on monomers linked through reversible connections having the capacity to undergo spontaneous and continuous changes in their constitution by exchange, reshuffling, incorporation and decorporation of various monomeric components.