Periodic Reporting for period 2 - SCORE (Swift COronavirus therapeutics REsponse)
Okres sprawozdawczy: 2021-04-01 do 2022-09-30
The COVID-19 pandemic and the SCORE consortium
Immediately after the start of the pandemic, major efforts were launched to rapidly produce effective vaccines, which indeed became available at unprecedented speed and contributed importantly to reduce the impact of COVID-19 worldwide. However, from the beginning, it was also clear that additional tools would be needed to counter this virus, which rapidly began to escape the immunity induced by both vaccination and natural infection on the basis of the evolutionary plasticity of its Spike protein.
Antiviral drugs arguably are the most important additional asset in the pandemic preparedness toolbox, as they can be used both therapeutically (to treat COVID-19 patients) and prophylactically, to protect people coming in direct contact with infected individuals (e.g. health care workers, frontline workers and teachers). By reducing virus shedding by infected patients, their direct contacts could be protected as well. Sufficiently potent antiviral drug treatment should help to reduce the R0 to below 1, which would be an essential for worldwide efforts to curb the pandemic.
It was against this background that the SCORE consortium (for SWIFT CORONAVIRUS THERAPEUTICS RESPONSE) was established in February 2020, to respond to one of the first EU calls for research proposals to counter the rapidly spreading SARS-CoV-2. The early realization that potent small-molecule antiviral drugs might be crucial to fully control this rapidly evolving RNA virus brought together eight academic and industrial partners (see table below), with extensive expertise in coronavirus research and antiviral drug development. In part the consortium was built on pre-existing collaborations that went back to the response to the SARS-CoV outbreak of 2002-2003 (EU projects SARS-DTV and VIZIER) and the emergence of MERS-CoV (EU projects SILVER, EUVIRNA and ANTIVIRALS).
Immediately after the start of the pandemic, major efforts were launched to rapidly produce effective vaccines, which indeed became available at unprecedented speed and contributed importantly to reduce the impact of COVID-19 worldwide. However, from the beginning, it was also clear that additional tools would be needed to counter this virus, which rapidly began to escape the immunity induced by both vaccination and natural infection on the basis of the evolutionary plasticity of its Spike protein.
Antiviral drugs arguably are the most important additional asset in the pandemic preparedness toolbox, as they can be used both therapeutically (to treat COVID-19 patients) and prophylactically, to protect people coming in direct contact with infected individuals (e.g. health care workers, frontline workers and teachers). By reducing virus shedding by infected patients, their direct contacts could be protected as well. Sufficiently potent antiviral drug treatment should help to reduce the R0 to below 1, which would be an essential for worldwide efforts to curb the pandemic.
It was against this background that the SCORE consortium (for SWIFT CORONAVIRUS THERAPEUTICS RESPONSE) was established in February 2020, to respond to one of the first EU calls for research proposals to counter the rapidly spreading SARS-CoV-2. The early realization that potent small-molecule antiviral drugs might be crucial to fully control this rapidly evolving RNA virus brought together eight academic and industrial partners (see table below), with extensive expertise in coronavirus research and antiviral drug development. In part the consortium was built on pre-existing collaborations that went back to the response to the SARS-CoV outbreak of 2002-2003 (EU projects SARS-DTV and VIZIER) and the emergence of MERS-CoV (EU projects SILVER, EUVIRNA and ANTIVIRALS).
The SCORE drug development pipeline
The pre-pandemic collaborative coronavirus studies of the SCORE partners covered a number of areas. Among them were structure-function analysis of a range of coronavirus nonstructural proteins and the Spike protein, studies of a range of (potentially druggable) virus-host interactions, structure-based drug design efforts, and many collaborations leading to the development of an extensive coronavirus toolbox and various compounds in (early) pre-clinical development. The latter were included in the SCORE drug development pipeline from the start, while other efforts focused on the screening of large chemical libraries, the targeted development of new or better inhibitors of specific viral enzymes, and the generation of SARS-CoV-2 specific molecular tools and assays. These tools included biochemical and biological assays, virus strains, reverse genetics systems, animal models and a range of protocols, and their development was facilitated by our vast experience with closely related coronaviruses.
Products developed within the SCORE consortium and tested in animal models:
The antiviral drug 13b-K, an inhibitor of the SARS-CoV-2 main protease
Compound series 06, an antiviral drug specifically inhibiting SARS-CoV-2
Compound series 08, a broad-spectrum coronavirus inhibitor which is further developed within the CARE consortium
HR targeting entry inhibitors for SARS-CoV-2
SAR405, an inhibitor of host factor VPS34 (a class III PI3K).
Suramin, a repurposed compound that inhibits SARS-CoV-2 replication and was used in combination with a new application method
The pre-pandemic collaborative coronavirus studies of the SCORE partners covered a number of areas. Among them were structure-function analysis of a range of coronavirus nonstructural proteins and the Spike protein, studies of a range of (potentially druggable) virus-host interactions, structure-based drug design efforts, and many collaborations leading to the development of an extensive coronavirus toolbox and various compounds in (early) pre-clinical development. The latter were included in the SCORE drug development pipeline from the start, while other efforts focused on the screening of large chemical libraries, the targeted development of new or better inhibitors of specific viral enzymes, and the generation of SARS-CoV-2 specific molecular tools and assays. These tools included biochemical and biological assays, virus strains, reverse genetics systems, animal models and a range of protocols, and their development was facilitated by our vast experience with closely related coronaviruses.
Products developed within the SCORE consortium and tested in animal models:
The antiviral drug 13b-K, an inhibitor of the SARS-CoV-2 main protease
Compound series 06, an antiviral drug specifically inhibiting SARS-CoV-2
Compound series 08, a broad-spectrum coronavirus inhibitor which is further developed within the CARE consortium
HR targeting entry inhibitors for SARS-CoV-2
SAR405, an inhibitor of host factor VPS34 (a class III PI3K).
Suramin, a repurposed compound that inhibits SARS-CoV-2 replication and was used in combination with a new application method
The secret of SCORE’s success?
The SCORE project has been operational from April 2020 up to October 2022, and covered the period during which rapidly evolving SARS-CoV-2 variants continued to appear and replace each other worldwide. The eight SCORE partners worked during this challenging period, with national lock-down periods, infected scientists and severe shortages in lab equipment, and lack of direct personal interactions and possibilities to recruit new scientists due to international travel restrictions.
Due to the scientific expertise, motivation, and highly successful collaboration the SCORE consortium succeeded to develop six different antiviral products until technological readiness level TRL 6 (proof of concept studies in animal models), established an extensive toolbox of which the products, reagents and technologies were readily shared between all partners, and the publication of 35 scientific articles, with another 4 submitted at this moment (September 2022). Another 10 SCORE publications are expected to be submitted in the coming year, and the latest publication update is always available under: https://www.score-cov.eu/Article/Publications. One SCORE patent has also been filed. Another very important asset has been the training of new SCORE scientific staff in developing antiviral drugs against an emerging pathogenic virus, under very difficult conditions. These people will represent an important reservoir of veteran pandemic preparedness scientists, with the motivation and training to tackle any new pandemic.
What was the basis for the success of the relatively small SCORE consortium? …..
A history of productive pre-existing collaborations in previous European consortia
A team of academic partners with highly complementary scientific expertise
Excellent understanding of each other’s scientific interests and technological capabilities
Easy sharing of toolbox instruments, products and technologies between partners
A small and flexible network, with the ability to quickly adapt to newly arising problems
Regular virtual meetings and presentations
An informal and efficient management structure, facilitated by the modest size of the SCORE consortium
A strongly committed, experienced and highly knowledgeable Scientific Advisory Board
Outlook
Despite the success of SCORE, and many other worldwide research activities and projects targeting SARS-CoV-2, it is clear that the (potential) impact of a viral pandemic on society and economy had been underestimated for several decades. The COVID-19 pandemic overwhelmed health systems when it turned out that – unlike SARS-CoV in 2002/2003 – this rapidly spreading (and evolving) respiratory viral agent could not be contained using basic control measures like isolation and quarantine. Antiviral drugs, if available, can have a major impact on the early control of a local outbreak of a newly emerging virus, whether a coronavirus or a member of one of the other high-risk virus families that have a record of successful zoonotic transmission events.
The clear lesson of the COVID-19 pandemic is that vaccine and drug development should move forward, especially in ‘peace time’ and supported by relatively modest but continuous investments. This will allow the steady development of basic virus knowledge and better technological starting points to counter infections with a range of high-risk virus families. It would be important to avoid interruptions of successful collaborative antiviral research due to funding gaps. In this sense, the COVID-19 pandemic has revealed a strong need for the development of a roadmap for the design, evaluation and production of (broad-spectrum) antiviral drugs. All members of the SCORE consortium remain eager to contribute to this goal on the basis of there established expertise in the area of virology, biochemistry, structural biology and/or medicinal chemistry.
The SCORE project has been operational from April 2020 up to October 2022, and covered the period during which rapidly evolving SARS-CoV-2 variants continued to appear and replace each other worldwide. The eight SCORE partners worked during this challenging period, with national lock-down periods, infected scientists and severe shortages in lab equipment, and lack of direct personal interactions and possibilities to recruit new scientists due to international travel restrictions.
Due to the scientific expertise, motivation, and highly successful collaboration the SCORE consortium succeeded to develop six different antiviral products until technological readiness level TRL 6 (proof of concept studies in animal models), established an extensive toolbox of which the products, reagents and technologies were readily shared between all partners, and the publication of 35 scientific articles, with another 4 submitted at this moment (September 2022). Another 10 SCORE publications are expected to be submitted in the coming year, and the latest publication update is always available under: https://www.score-cov.eu/Article/Publications. One SCORE patent has also been filed. Another very important asset has been the training of new SCORE scientific staff in developing antiviral drugs against an emerging pathogenic virus, under very difficult conditions. These people will represent an important reservoir of veteran pandemic preparedness scientists, with the motivation and training to tackle any new pandemic.
What was the basis for the success of the relatively small SCORE consortium? …..
A history of productive pre-existing collaborations in previous European consortia
A team of academic partners with highly complementary scientific expertise
Excellent understanding of each other’s scientific interests and technological capabilities
Easy sharing of toolbox instruments, products and technologies between partners
A small and flexible network, with the ability to quickly adapt to newly arising problems
Regular virtual meetings and presentations
An informal and efficient management structure, facilitated by the modest size of the SCORE consortium
A strongly committed, experienced and highly knowledgeable Scientific Advisory Board
Outlook
Despite the success of SCORE, and many other worldwide research activities and projects targeting SARS-CoV-2, it is clear that the (potential) impact of a viral pandemic on society and economy had been underestimated for several decades. The COVID-19 pandemic overwhelmed health systems when it turned out that – unlike SARS-CoV in 2002/2003 – this rapidly spreading (and evolving) respiratory viral agent could not be contained using basic control measures like isolation and quarantine. Antiviral drugs, if available, can have a major impact on the early control of a local outbreak of a newly emerging virus, whether a coronavirus or a member of one of the other high-risk virus families that have a record of successful zoonotic transmission events.
The clear lesson of the COVID-19 pandemic is that vaccine and drug development should move forward, especially in ‘peace time’ and supported by relatively modest but continuous investments. This will allow the steady development of basic virus knowledge and better technological starting points to counter infections with a range of high-risk virus families. It would be important to avoid interruptions of successful collaborative antiviral research due to funding gaps. In this sense, the COVID-19 pandemic has revealed a strong need for the development of a roadmap for the design, evaluation and production of (broad-spectrum) antiviral drugs. All members of the SCORE consortium remain eager to contribute to this goal on the basis of there established expertise in the area of virology, biochemistry, structural biology and/or medicinal chemistry.
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