COVID-19 - Coronavirus disease 2019

Accelerated Structural Genomics on CoViD-19 – AcceS-Ge CoViD-19

Submission summary

Starting late December 2019, the emergence of an uncharacterized pathogen appeared from the city of Wuhan, China. Since then, the identified CoViD-19 virus propagated worldwide, infecting tens of thousands of humans and killing thousands. The countries suffering the most from the infectious disease adopted a full confinement protocol. Prior the lengthy elaboration of an approved vaccine, antiviral molecules can be elaborated to inhibit the viral cycle. Developing such molecules requires the knowledge of the atomic resolution structures of most of the virus macromolecules in order to target their specific functions. Several well-known methods are dedicated to structure determination, among which X-ray crystallography, electron microscopy and NMR spectroscopy. All of these technique present pros and cons, yet remain dependent of time-consuming high-quality sample preparation. In a highly time constraint worldwide pandemic situation, these methods have to be fastened while keeping their results within the highest quality standards.

One way to speed up macromolecular X-ray diffraction methods lies in innovative sample preparation. The isolation of protein crystals naturally occurring inside cells and organisms has opened a window for a new type of macromolecular crystallography (MX) and structural biology. The emergence of new approaches in MX, such as the in vivo crystallography (ivMX), coupled to state-of-the-art instrumentations for sample handling and delivery to upgraded light sources breaks the classically encountered bottlenecks of structural biology. The needs for sample purification prior crystallization and the requirement of large crystals for high quality diffraction data collection are removed, accelerating the process of structure determination via very high throughput structural genomics.

In the last 5 years, the biology and health scientific Section of Synchrotron SOLEIL (hereafter referred as SOLEIL) has successfully integrated a complete pipeline for ivMX. It includes all the steps from cloning the sequences for the samples of interests in a large set of predefined expression plasmids identified from the ivMX-plasmid library; heterologous expression within human HEK293-FS cells for in-vivo protein crystal formation; identification and isolation of positive crystal hits by coupling Secondary Harmonic Generation-based microscopy with microfluidics-based sample handling; robot-assisted X-ray diffraction experiments on the crystal-containing cells; data analysis and structure determination facilitated by high-standard clustered computing.

In the current project, we propose to clone the entire set of proteins coded by the CoViD-19 pathogen (up to 27 identified so far ) and run their full length form as well as their respective relevant domains in our accelerated pipeline for structural genomics. Following these developments, positive hits will be brought to structure determination and eventually will serve as target for structure-based drug-design studies. These advances should help understanding better the virus, its pathogenicity, and initiate the development of CoViD-19 antiviral drugs.

Project coordination

Leonard Chavas (Synchrotron SOLEIL)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

VIM INRAE
SANOFI SANOFI
SOLEIL Synchrotron SOLEIL

Help of the ANR 59,432 euros
Beginning and duration of the scientific project: April 2020 - 12 Months

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