Community Research and Development Information Service - CORDIS

Novel synthetic influenza inhibitors

Influenza is a contagious respiratory disease caused by the influenza A virus. The threat of influenza pandemics and the emergence of drug-resistant viruses necessitates the development of new antiviral drugs.
Novel synthetic influenza inhibitors
Influenza A virus is an RNA virus enclosed within a lipoprotein envelope, which contains two membrane glycoproteins, hemagglutinin (HA) and neuraminidase (NA). HA recognises and binds to cell surface receptors with terminal sialic acid residues while NA cleaves the receptor, releasing influenza virions from the infected cells.

Significant effort has been dedicated to the development of vaccines against HA and antivirals targeting NA. However, given the capacity of the virus to mutate, vaccine efficacy can be compromised and antivirals requires annual re-design to match HA variations. In terms of influenza A antivirals, the most successful drugs mimic the sialic acid natural substrate that binds in the active site of NA. However, the emergence of drug-resistant strains necessitates alternative drugs with novel structural motifs and substitution patterns.

Towards this goal, the EU-funded G1_G2_NAINHIBIT (Design, synthesis and evaluation of potential group-1 and group-2 neuraminidase inhibitors) project utilised a bicyclic analogue of sialic acid as a scaffold for generating new NA inhibitors. The idea was to functionalise the scaffold with different groups that more efficiently target the catalytic site of the enzyme.

With the help of molecular modelling, researchers proposed a number of new structures with different functionalisation and established a simplified synthetic route for producing these derivatives. Additional functionalisation was proposed to increase the affinity to the NA 150-cavity, an additional binding region present in close proximity to the NA active site. However, the positioning of functional groups on the proposed system requires further tuning to produce strong interactions within the catalytic site.

Nonetheless, the G1_G2_NAINHIBIT team developed and optimised the methodology for synthesising highly functionalised and structurally complex molecules. The project results further support the use of a sialic acid mimic as a scaffold for interacting with the NA active site during catalysis.

Related information

Subjects

Life Sciences

Keywords

Influenza, hemagglutinin, neuraminidase, sialic acid, inhibitors, G1_G2_NAINHIBIT
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