Developing non-carbohydrate glycomimetics targeted to bacterial lectins

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Protein-carbohydrate interactions play a key role in the first step of numerous biological processes, e.g. fertilization and tissue homing of immune cells, but also in infection, inflammation, migration of tumor cells and other pathologies. Pathogenic microorganisms (viruses, bacteria, fungi and parasites) have developed strategies for utilizing glycan epitopes on human tissues for specific recognition, for adhesion and sometimes for cellular internalization. The proteins involved can be viral capsid domains, adhesins on top of pili, soluble lectins or carbohydrate binding domains of enzymes or toxins. Their carbohydrate-binding sites are specific for glycans located on human epithelia such as the histo/blood group oligosaccharides of ABO and Lewis systems. Molecules that could interfere with such lectin/glycan interaction are therefore of high interest as anti-infectious agents. Similarly human lectins are involved in chronic diseases related to inflammation and cancer, and consequently the search for lectin inhibitors to interfere with these pathological conditions is of outstanding interest. The project aims at the development of the underexplored area of non-carbohydrate drug-like lectin inhibitors. Such glycomimetics could overcome current limitations of carbohydrate-based therapeutics such as pharmacokinetic and pharmacodynamic limitations as well as synthetic tractability. Targeting three lectins from opportunistic bacteria, the consortium of two French and two German laboratories proposes to combine virtual and in vitro screening of chemical libraries using functional assays and NMR approaches, followed by structure (X-ray, NMR), thermodynamics (ITC) and kinetics (SPR, MD) guided lead optimization. Assembling of lead structures into oligomeric compounds in order to use natural lectin multivalency to gain very high affinity will be also envisaged. This project aims at the establishment of a broadly applicable methodology for the development of non-carbohydrate lectin inhibitors. A set of three diverse and representative bacterial lectins was chosen to explore the potential of the discovery pipeline. However, this approach will not be limited to bacterial targets and other viral, fungal, or human lectins of high therapeutic significance can be targeted as well. While pipeline development is our major concern, generating novel anti-infectives is foreseen (i.e. a problem-solving endeavor). Moreover, this endeavor will contribute to our fundamental understanding of biological processes involving multivalent receptors such as membrane dynamics and lipid raft-mediated internalization (i.e. a curiosity driven research).