Periodic Reporting for period 1 - EvaMobs (Evolvable and rapidly adaptable monobodies: a broad-spectrum antiviral platform)
Berichtszeitraum: 2024-01-01 bis 2025-06-30
With progress in globalization, expansion of human populations into natural habitats, and aggravation of climate change comes an increased risk of viral outbreaks. As demonstrated by the COVID-19 pandemic, not being prepared for such events has devastating consequences on public health, society and the economy.
EvaMobs will improve preparedness of the European Union (EU) for the next viral outbreak(s) of pandemic potential by developing a platform for the discovery, development, production and validation of evolvable and rapidly adaptable antivirals (Figure). These innovative medicines will be based on small human-derived proteins called monobodies (Mobs). To demonstrate the capacity of this platform is initially being applied to four pathogenic viruses with epidemic and/ or pandemic potential: Influenza A, SARS-CoV-2, respiratory syncytial virus, and Zika virus. Using deep learning and computational design tools, we are generating tailor-made Mobs and other viral-blocking proteins and elucidating the molecular details of their binding interactions using cryo-EM. Simple bacterial expression of Mobs, the development of a semi-automated high-throughput screening platform for evaluation of the Mobs’ stability and target affinity and streamlined in vitro and in vivo preclinical validation, will allow rapid development and selection of stable and potently neutralizing candidates. The antiviral protein with the best preclinical indicators will then be tested in a phase I clinical trial after implementing stable formulation and GMP production.
These antiviral proteins that can be tailored to have a high affinity for any type of virus, so, by precisely modifying the Mobs framework, this technology enables the rapid development of customized molecules capable of targeting newly emerging pandemic viruses and viral variants. Therefore, EvaMobs provides an innovative, robust and flexible platform for antiviral biologics development as well as a diverse portfolio of validated drugs, strengthening the EU’s pandemic preparedness.
EvaMobs will improve preparedness of the European Union (EU) for the next viral outbreak(s) of pandemic potential by developing a platform for the discovery, development, production and validation of evolvable and rapidly adaptable antivirals (Figure). These innovative medicines will be based on small human-derived proteins called monobodies (Mobs). To demonstrate the capacity of this platform is initially being applied to four pathogenic viruses with epidemic and/ or pandemic potential: Influenza A, SARS-CoV-2, respiratory syncytial virus, and Zika virus. Using deep learning and computational design tools, we are generating tailor-made Mobs and other viral-blocking proteins and elucidating the molecular details of their binding interactions using cryo-EM. Simple bacterial expression of Mobs, the development of a semi-automated high-throughput screening platform for evaluation of the Mobs’ stability and target affinity and streamlined in vitro and in vivo preclinical validation, will allow rapid development and selection of stable and potently neutralizing candidates. The antiviral protein with the best preclinical indicators will then be tested in a phase I clinical trial after implementing stable formulation and GMP production.
These antiviral proteins that can be tailored to have a high affinity for any type of virus, so, by precisely modifying the Mobs framework, this technology enables the rapid development of customized molecules capable of targeting newly emerging pandemic viruses and viral variants. Therefore, EvaMobs provides an innovative, robust and flexible platform for antiviral biologics development as well as a diverse portfolio of validated drugs, strengthening the EU’s pandemic preparedness.
EvaMobs overall objectives are:
1. To develop an innovative structure-based computational framework for the discovery of antiviral Mobs
2. To implement a robust pipeline for the production, stabilization and screening of antiviral Mobs
3. To perform a preclinical validation of antiviral Mobs
4. To validate a selected Mob in a phase I clinical trial to ensure clinical translation of the project results
In the first eighteen months, EvaMobs achieved the following steps:
✓ Improved protein design protocols have been developed for the design of monobodies (Mobs). The four proof-of-concept viruses were targeted in parallel and more than 6000 Mob designs were added to the EvaMobs database.
✓ Good progress was achieved in the structure characterization of Mobs bound to viral proteins using Cryo-EM experiments.
✓ Several viral proteins were successfully produced, and effective screening strategies were implemented for screening stable Mobs with high affinity.
✓ Neutralization and half-life of antiviral proteins were tested. Pre-clinical validation is being performed at a fast pace with promising results to be shared soon.
1. To develop an innovative structure-based computational framework for the discovery of antiviral Mobs
2. To implement a robust pipeline for the production, stabilization and screening of antiviral Mobs
3. To perform a preclinical validation of antiviral Mobs
4. To validate a selected Mob in a phase I clinical trial to ensure clinical translation of the project results
In the first eighteen months, EvaMobs achieved the following steps:
✓ Improved protein design protocols have been developed for the design of monobodies (Mobs). The four proof-of-concept viruses were targeted in parallel and more than 6000 Mob designs were added to the EvaMobs database.
✓ Good progress was achieved in the structure characterization of Mobs bound to viral proteins using Cryo-EM experiments.
✓ Several viral proteins were successfully produced, and effective screening strategies were implemented for screening stable Mobs with high affinity.
✓ Neutralization and half-life of antiviral proteins were tested. Pre-clinical validation is being performed at a fast pace with promising results to be shared soon.
• EvaMobs developed a computational design framework, integrating structure-based design with high-throughput screening, which is iteratively being refined based on experimental validation.
• Biophysical characterization including structural determination and stability and binding affinity evaluation is providing detailed insight into Mob–virus complexes and their neutralization mechanisms.
• EvaMobs is setting up a robust preclinical validation pipeline: design → production → screening → in vivo validation, which can be applied to new viruses.
• Biophysical characterization including structural determination and stability and binding affinity evaluation is providing detailed insight into Mob–virus complexes and their neutralization mechanisms.
• EvaMobs is setting up a robust preclinical validation pipeline: design → production → screening → in vivo validation, which can be applied to new viruses.