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ComplexINC technologies key to influenza polymerase structure discovery

ComplexINC conceptualizes and systematically generates advanced toolkits for de novo assembly of complex biologics and metabolic pathways in eukaryotic expression systems, making hitherto elusive high-value biologics accessible for academic and industrial R&D. A much sought-after yet elusive target for structure-based drug discovery is influenza polymerase. ComplexINC’s MultiBac and ComplexLINK technologies now synergized to enable, for the first time, its production and structure determination.

Influenza, commonly known as ‘flu’, is a seasonal infectious disease which many of us encounter every year. Typical symptoms include a running nose, the occasional cough, and elevated temperature. However, by altering its genetic material, the virus that causes influenza can rapidly evolve into a deadly killer, which has historically given unpredictable rise to millions of deaths and massive socio-economic damage. In fact, the Spanish flu that ravaged Europe in 1918 claimed more victims then the carnage during all four years of World War I combined. Further examples of flu outbreak include the recent bird and swine flu pandemics. Presently available vaccination strategies against flu are only moderately effective. Despite its common appearance, a detailed understanding of the molecular mechanisms of influenza has remained enigmatic. More than 40 years ago, the influenza polymerase was discovered, a key protein complex that replicates the genetic material of the virus. Atomic resolution information on the structure and function of this protein machine is essential, as it may open up important avenues for drug discovery. However, the influenza polymerase remained inaccessible for decades. This has now changed dramatically. In the current online issue of Nature, structures of influenza polymerase complex are presented, determined by X-ray crystallography. The break-through studies, led by Stephen Cusack, renowned influenza expert and Head of the EMBL Grenoble Outstation, provide unprecedented insight into the inner workings of this viral protein machine. This revolution in understanding influenza was catalyzed by ComplexLinkTM, a disruptive new methodology to produce hitherto not accessible protein complexes. By using ComplexLinkTM, it became possible, for the first time, to produce influenza polymerase recombinantly, in the quality and quantity required for high-resolution structural and functional analysis. 'It was evident that new technology was required to get hold of influenza polymerase to unlock its secrets, given the very major but futile effort expended over decades by some of the foremost researchers world-wide.' says Imre Berger, ComplexINC coordinator and inventor of the ComplexLinkTM technology. The solution came from observing other viruses, such as Coronavirus, the agent that causes respiratory syndrome (SARS). Coronavirus does not produce its protein repertoire from individual genes that are translated into proteins as most organisms do. Instead, Coronavirus efficiently produces its proteome via long contiguous chains in which its proteins are linked together like pearls on a string. A highly specific molecular scissor - a protease - then tailors these large polyprotein chains by precisely cutting out the individual, functional proteins. ComplexLinkTM recapitulates this powerful approach in cell culture in the laboratory. 'It is quite remarkable, that an unrelated virus provided the decisive clue how to solve the flu polymerase production problem that has impeded the field for so long, and that it worked so surprisingly well' states Ismail Moarefi, CSO of Crelux and Joint Coordinator of ComplexINC. Ismail’s team successfully develops 2nd generation ComplexLinkTM systems, to directly accelerate Crelux’ drug discovery programs. 'These fantastic structures could be of immense value for pharmacological R&D and provide entirely novel leads to develop new and better drugs to combat influenza.' ComplexLinkTM is commercialized by ComplexINC spinoff Geneva Biotech, which already markets a number of new technologies that are part of the ComplexINC project. 'We have as our top priority to provide solutions for important technical challenges, to advance research and development in medicine and industrial biotechnology.” concludes Daniel Fitzgerald, CEO of Geneva Biotech. “These studies outstandingly showcase the aptitude of our innovative technologies.'

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