Periodic Reporting for period 1 - PANVIPREP (Developing broad-spectrum antiviral drugs for pandemic preparedness)
Período documentado: 2024-01-01 hasta 2025-06-30
Developing broad-spectrum antiviral drugs for pandemic preparedness.
The threat of virus epidemics continues to increase at an alarming rate. Across recent decades, a range of RNA virus pathogens has emerged from wildlife, or has re-emerged. Pathogens with pandemic potential, like SARS-coronavirus-2, can have worldwide impact by affecting personal and public health, and disrupting the economy and society. This threat is increasing due to societal, ecological, and economic factors. An additional complication is the unpredictable evolution of RNA viruses, which are masters at rapidly adapting to changing circumstances. Therefore, we must understand the risks posed by these viruses and take steps to protect our health, economy, and society.
While vaccination can effectively control viral diseases, there will always be a time gap before a vaccine can be produced and distributed. In this context, directly acting antiviral drugs (i.e. drugs targeting conserved and essential functions in virus replication) offer an important but underappreciated possibility for prophylactic and therapeutic intervention. They will allow the immediate treatment of infected patients and may save the lives of those falling critically ill. As they will reduce virus shedding by these early patients, the R0 may be pushed below 1, which would be an essential contribution to efforts to curb an epidemic.
The conserved nature of many of the targets of directly acting antiviral drugs (like the active sites of viral proteases and polymerases) enhances the chance of broad(er)-spectrum activity because these targets are much less subjected to direct immune selection and tend to evolve more slowly due to structure-function constraints. Thus, directly-acting antiviral drugs can be a critical tool to reduce the impact of virus outbreaks in their earliest phase or even to contain them before becoming a more widespread problem.
The PANVIPREP consortium incorporates 14 European partners with complementary expertise in virology, structural biology, medicinal chemistry, pharmacology, and machine-learning approaches. Together, they aim to contribute to antiviral pandemic preparedness by piloting and progressing antiviral drug development, in particular through
- developing and advancing broad(er)-spectrum antiviral compounds targeting five selected RNA virus families with high epidemic or pandemic potential;
- delivering novel RNA virus knowledge and tools, including molecules that block novel molecular targets in the viral replication cycle;
- implementing technological innovations to accelerate antiviral drug discovery and development.
The threat of virus epidemics continues to increase at an alarming rate. Across recent decades, a range of RNA virus pathogens has emerged from wildlife, or has re-emerged. Pathogens with pandemic potential, like SARS-coronavirus-2, can have worldwide impact by affecting personal and public health, and disrupting the economy and society. This threat is increasing due to societal, ecological, and economic factors. An additional complication is the unpredictable evolution of RNA viruses, which are masters at rapidly adapting to changing circumstances. Therefore, we must understand the risks posed by these viruses and take steps to protect our health, economy, and society.
While vaccination can effectively control viral diseases, there will always be a time gap before a vaccine can be produced and distributed. In this context, directly acting antiviral drugs (i.e. drugs targeting conserved and essential functions in virus replication) offer an important but underappreciated possibility for prophylactic and therapeutic intervention. They will allow the immediate treatment of infected patients and may save the lives of those falling critically ill. As they will reduce virus shedding by these early patients, the R0 may be pushed below 1, which would be an essential contribution to efforts to curb an epidemic.
The conserved nature of many of the targets of directly acting antiviral drugs (like the active sites of viral proteases and polymerases) enhances the chance of broad(er)-spectrum activity because these targets are much less subjected to direct immune selection and tend to evolve more slowly due to structure-function constraints. Thus, directly-acting antiviral drugs can be a critical tool to reduce the impact of virus outbreaks in their earliest phase or even to contain them before becoming a more widespread problem.
The PANVIPREP consortium incorporates 14 European partners with complementary expertise in virology, structural biology, medicinal chemistry, pharmacology, and machine-learning approaches. Together, they aim to contribute to antiviral pandemic preparedness by piloting and progressing antiviral drug development, in particular through
- developing and advancing broad(er)-spectrum antiviral compounds targeting five selected RNA virus families with high epidemic or pandemic potential;
- delivering novel RNA virus knowledge and tools, including molecules that block novel molecular targets in the viral replication cycle;
- implementing technological innovations to accelerate antiviral drug discovery and development.
Expanding and exploiting our knowledge of the ‘antivirome’.
PANVIPREP will combine conventional methods for drug discovery and development with a number of innovative approaches and improved methodologies. A three-track approach to identify and improve antiviral hits. To identify and improve potent drug-like compounds, we will employ three parallel approaches in work packages 2, 3 and 4:
WP2 - From hit to early lead: development of selected hit series
WP3 - From hit to new target: target identification and evaluation by exploratory chemistry & innovative drug design approaches
WP4 - From target to new hits: exploring established viral drug targets to discover innovative drug approaches
This integrated approach closes the drug discovery loop and will deliver better starting points for future drug development. Simultaneously, novel technological approaches will be incorporated in a robust pipeline for broad-spectrum antiviral drug development. Data files will be formatted to enable AI-based approaches involving PANVIPREP partners from multiple scientific disciplines. We aim to radically reduce the time and cost of new hit discovery. Building a model trained to perform a supervised analysis on pre-existing data sets can identify novel chemistry in virtual libraries, which are more likely to be active antiviral hits.
PANVIPREP will combine conventional methods for drug discovery and development with a number of innovative approaches and improved methodologies. A three-track approach to identify and improve antiviral hits. To identify and improve potent drug-like compounds, we will employ three parallel approaches in work packages 2, 3 and 4:
WP2 - From hit to early lead: development of selected hit series
WP3 - From hit to new target: target identification and evaluation by exploratory chemistry & innovative drug design approaches
WP4 - From target to new hits: exploring established viral drug targets to discover innovative drug approaches
This integrated approach closes the drug discovery loop and will deliver better starting points for future drug development. Simultaneously, novel technological approaches will be incorporated in a robust pipeline for broad-spectrum antiviral drug development. Data files will be formatted to enable AI-based approaches involving PANVIPREP partners from multiple scientific disciplines. We aim to radically reduce the time and cost of new hit discovery. Building a model trained to perform a supervised analysis on pre-existing data sets can identify novel chemistry in virtual libraries, which are more likely to be active antiviral hits.
The potential impact of broad(er)-spectrum antiviral therapy in possible future epidemic situations was illustrated in a recent COVID-19 modelling study by partner KU Leuven. This concerned the use of antiviral drugs to control a local outbreak compared the impact of purely non-pharmaceutical interventions. The study concluded that antiviral drug treatment, in particular when started early, can have a major impact on the peak of infectiousness of an infected person. When combined with contact tracing, quarantine and isolation, this will prominently increase the probability that the outbreak will fade out.
PANVIPREP aims to identify and explore the most suitable targets for broad(er)-spectrum antiviral drug discovery and development. The project contains a crucial feedback loop: information from mode-of-action and target evaluation studies will fuel additional target-based drug discovery, thus expanding the hit portfolio and helping to define the best hit series for further development. For each virus group, these efforts will further increase our understanding of their ‘antivirome’, the collective set of viral targets amenable to inhibition by small-molecule compounds.
In the coming decade, we foresee a paradigm change: massive global antiviral datasets will become available (consisting of information on viruses, infected cell-based assays, viral targets, compounds, PK and tox data) in combination with new high-resolution structural models (X-Ray/Cryo-EM) and improved virtual screening methods. This “antiviral data cloud” will be an extraordinary substrate for AI to predict and propose high-content focused libraries. We anticipate that hit rates from phenotypic and enzymatic assays will continuously increase in the coming years.
PANVIPREP aims to identify and explore the most suitable targets for broad(er)-spectrum antiviral drug discovery and development. The project contains a crucial feedback loop: information from mode-of-action and target evaluation studies will fuel additional target-based drug discovery, thus expanding the hit portfolio and helping to define the best hit series for further development. For each virus group, these efforts will further increase our understanding of their ‘antivirome’, the collective set of viral targets amenable to inhibition by small-molecule compounds.
In the coming decade, we foresee a paradigm change: massive global antiviral datasets will become available (consisting of information on viruses, infected cell-based assays, viral targets, compounds, PK and tox data) in combination with new high-resolution structural models (X-Ray/Cryo-EM) and improved virtual screening methods. This “antiviral data cloud” will be an extraordinary substrate for AI to predict and propose high-content focused libraries. We anticipate that hit rates from phenotypic and enzymatic assays will continuously increase in the coming years.