New chemistries of SIALIc acid targeting the FLU virus – SIALIFLU

- New ligands specifically targeting group 1 neuraminidases:
1- Development of focused ligand libraries by molecular modeling,
2- Synthesis of the selected compounds using palladium-catalysed allylic substitution.
- Reductive samariation of sialic acids

- Synthesis of a small library of ligands, as proposed by molecular modeling.
- Biological evaluation of these ligands on N1-, N4-, N5- or N8-type viruses. No inhibitory - activity could be evidenced.
- Conformational equilibrium study of glycal-type compounds using quantum chemistry methods.
- Reductive cyclization on the anomeric center of sialic acid promoted by samarium diiodide

- De novo synthesis of derivatives modified at the C-6 position and possessing a phosphonate group instead of a carboxylate and targeting neuraminidase (boron chemistry).
- Preparation of a collection of new C-sialoside multimers using the cycloaddition between alkyne and azide
- Free energy calculations of 150-loop Cavity Opening of the neuraminidase enzyme.

Conformational study of glycal-type neuraminidase inhibitors. Surpateanu G.; Soulé J.-F.; Beau J.-M.; Norsikian S.; Iorga, B. I. J. Carbohydr. Chem. 2012, 31, 114-129.

Influenza of type A causes a severe viral infection of the respiratory system. It has been at the origin of some of the worst epidemics in the history of mankind and continues to be a major health concern. Although vaccination is the primary strategy for the prevention of influenza infections during epidemics, vaccine production by current methods cannot be carried out at the pace required to stop the progress of a new strain of the influenza virus. Also, recent alarming reports on the emergence of drug resistance make the development of new anti-influenza molecules a priority. Therefore, effective antiviral agents are required to prepare for a pandemic.

In this general context, it is our intention to develop a discovery program for new constructs specifically directed against hemagglutinin (H) and the enzyme neuraminidase (N), both crucial glycoproteins for the viral infection and important targets for drug development, with a special focus on the proteins of the H1N1 and H5N1 strains. The availability of such drugs would also make possible combined drug therapies to prevent the selection of resistant viruses. Infections by Influenza viruses of type A have a significant impact on public health and economy and therefore justify the availability of effective new generations of therapeutics to control viral outbreaks.

SIALIFLU specifically aims at discovering new selective binders of neuraminidase 1 that target the catalytic site as well as the newly identified "150-cavity" of the enzyme. The synthesis of new neuraminidase inhibitors will be based on a dihydropyranyl skeleton, utilizing palladium and boron chemistries. It is also intended to identify new multivalent constructs that efficiently interact with the hemagglutinin receptor. This second synthetic objective of this project will exploit samarium diiodide mediated coupling processes and reactions of the "click" chemistry. The chemistry work will be strongly associated and guided by modeling studies and enzymatic, binding and structural studies with the targeted proteins. In the course of this project in synthetic chemistry, we also anticipate the identification of new synthetic routes to sialic acids and derivatives as well as the unraveling of novel organometallic access to these important carbohydrates. There is intense research interest in sialic acid chemistry [N-acetylneuraminic acid (Neu5Ac) conjugates and modified structures] owing to its significant role in physiological processes and diseases.

To address this goal, we propose five complementary approaches in synthetic chemistry, molecular modeling and structural biology:
- The drug design by molecular modeling of inhibitors targeting the open conformation of neuraminidase 1,
- The synthesis of new derivatives targeting the open conformation of neuraminidase subtype 1 (Palladium and conjugate chemistry)
- The de novo synthesis of derivatives modified at the C-6 position and/or possessing a phosphonate polar group, targeting neuraminidase (Boron chemistry)
- The synthesis of robust C-sialoside multimers for hemagglutinin binding inhibition (Samarium and "click" chemistry)
- The structural biology on hemagglutinin and neuraminidase 1 and evaluation of the bio-activities of the newly prepared molecules.