products and technology
Savira employs rational, structure-based design of small molecule drugs targeting the influenza virus polymerase based on the inhibition of two distinct protein domains.
The influenza polymerase is a viral protein crucial in the genesis of new infectious virions. For genetic transcription, the viral polymerase uses a unique mechanism called ‘cap-snatching’, by which the virus ‘steals’ a part of the host cell RNA and uses it as primer for the production of its own, viral RNA. With this ‘feint’, the virus forces the infected cell to produce viral proteins eventually forming new infectious viral particles. Research by the EMBL identified the molecular architecture of both protein domains crucial for this mechanism, the cap-binding domain and the endonuclease-active site, laying the basis for Savira’s ambitious drug design programs.
A proprietary focused compound library with a broad range of individually structure-based designed and novel lead series has been generated. All compounds have been tested for biological activities in various in vitro assays and the most promising scaffold families have been protected worldwide by patent applications. Medicinal chemistry programs (hit identification as well as lead generation and optimization) have provided highly selective ligands with binding affinities being increased by several orders of magnitude and improved in vitro inhibition of influenza virus replication in infected cells. In vivo antiviral proof of concept in mice with lethal influenza virus infection was demonstrated for both, cap-binding and endonuclease inhibitors.
Besides the development of mono-selective cap-snatching inhibitors targeting the cap-binding domain and endonuclease active site of the influenza polymerase, Savira has recently focused on the design of dual ligands demonstrating activity against both of the above targets in a single molecule.