The National Institute of Allergy and Infectious Diseases (NIAID) is seeking applications to establish the Antiviral Drug Discovery (AViDD) program of multidisciplinary Centers focused on discovery and development of antivirals against coronaviruses (CoVs) and one or more select RNA viruses with pandemic potential.
Typical drug discovery programs require several years to progress from target validation through initial lead series identification and optimization to selection of a candidate drug for clinical trials. Therefore, if efforts are initiated only after an outbreak or pandemic occurs, it is unlikely that a virus-specific small-molecule therapeutic will be available within a useful timeframe to have clinical impact.
A potentially more effective approach is to invest drug discovery efforts aimed at building a more robust pipeline of antiviral lead series and drug candidates, so when a new outbreak or pandemic occurs, there will be more options available for clinical deployment. NIAID’s intention of the AViDD Centers is to support focused antiviral drug discovery efforts directed toward key viral pathogens or viral families and/or common drug targets or mechanisms-of-action with the aim of generating a more substantial pool of antiviral lead series and candidate drugs with the potential to address the immediate threat of Severe Acute Respiratory Syndrome CoV-2 (SARS-CoV-2), as well as provide antiviral drug candidates that might quickly pivot to address future viral outbreaks or pandemics. Of particular interest for this effort is identification and development of oral drug candidates with suitable safety profiles for broad use in the outpatient setting.
Each Center will encompass a multi-project multidisciplinary research platform that employs innovative virology, biochemistry, structural biology, medicinal chemistry, genomics and/or systems biology approaches to identify and select essential virus-specific targets for discovery and development of antivirals against CoVs. The platform will also provide for identification of conserved structures and functions that are shared between the selected CoVs and RNA viruses that will be targeted for antiviral development.
Based on targets defined for drug development, lead series and candidates will be identified through iterative cycles of evaluation and refinement using state-of-the-art screening technologies, structure-based design and medicinal chemistry. Subsequent advancement of inhibitors of viral functions to lead candidates will require specialized evaluations, including testing against live viruses in cell culture and animal models, as well as exploring the pharmacology and toxicology of the therapeutic candidates.
While early target identification and validation efforts in the Centers may be led by academic labs, NIAID requires Centers to include industry expertise actively participating in projects pursuing later-stage antiviral development to ensure access to high-quality chemical libraries and input of medicinal chemistry and pharmacology expertise.
Priority Viral Pathogens
Each AViDD Center supports a multi-project research platform directed towards discovery and development of antivirals targeting coronaviruses, with an emphasis on SARS-CoV-2, and one or more viral pathogens from the following RNA virus families of pandemic potential:
- Paramyxoviruses
- Bunyaviruses (Bunyavirales)
- Togaviruses
- Filoviruses
- Picornaviruses
- Flaviviruses
Although assays utilizing model systems (e.g. pseudoviruses or replicons) for early discovery are acceptable, lead development activities in the Centers must focus on targeting virulent members of the pathogens listed above under appropriate biosecurity and biosafety conditions.
Research Projects are expected to incorporate state-of-the-art technology and approaches and may include consortium arrangements for required activities. Applicants are encouraged to carefully consider the scope and range of research proposed and develop a Center that is coherent overall and consistent with available resources and personnel.
Example AViDD Centers
Center platforms and objectives may range from discovery and development of single or multiple antivirals targeting specific pathogens to development of modern technologies or platforms that target a wide array of pathogens, and activities may range from early basic and discovery-based efforts to late-stage preclinical development with industrial participation.
Examples of hypothetical AViDD Centers follow:
Drug Discovery Targeting Viral Replication
- Administrative Core
- Scientific Core: Animal model development and candidate antiviral evaluation
- Research Project 1: Identification and validation of novel replication targets
- Research Project 2: Essential viral enzymes as targets for novel drugs with pan-CoV activity
- Research Project 3: Discovery of novel lead series targeting Nipah or Hendra virus replication
- Research Project 4: Discovery of novel lead series targeting replication in filoviruses
- Research Project 5: Preclinical evaluation of SARS-CoV-2 replication inhibitors as oral drug candidates
Novel Targets for Antiviral Drug Discovery
- Administrative Core
- Scientific Core: Target-based and antiviral screening assays for priority RNA viruses
- Scientific Core: Structural biology with representative targets from priority RNA viruses
- Research Project 1: Viral assembly processes as targets for novel drug discovery
- Research Project 2: Discovery of novel nucleoside/tide drugs with potential broad-spectrum antiviral activity
- Research Project 3: Identification and validation of novel (non-polymerase) targets important in viral lifecycles
- Research Project 4: Artificial-Intelligence to identify novel targets and drugs that inhibit viral lifecycles
- Research Project 5: Discovery of novel lead series targeting viral enzymes essential for replication
Novel Antiviral Drugs Targeting Proteases
- Administrative Core
- Scientific Core: Target-based and antiviral screening assays for priority RNA viruses
- Scientific Core: Medicinal chemistry for rapid expansion of SAR for lead series
- Research Project 1: Viral proteases as targets for novel drug discovery
- Research Project 2: Repositioning known antiviral protease inhibitors for pan-CoV activity
- Research Project 3: Harnessing host protein degradation pathways to discover novel inhibitors of viral proteases
- Research Project 4: Comparative Structural Biology of viral proteases to inform drug discovery
- Research Project 5: Preclinical Evaluation of SARS-CoV-2 drug leads targeting viral proteases
The following types of studies will be not be considered for this effort:
- Projects that do not target coronaviruses (including SARS-CoV-2) and one or more pathogens from the viral families listed above.
- Antiviral approaches that block host targets or modulate host immune-response.
- Projects proposing the discovery and/or development of therapeutic monoclonal antibodies (mAbs), therapeutic polyclonal antibodies or plasma-based therapeutics.
- Projects proposing the discovery and/or development of a vaccine.
- Projects proposing repurposing of an FDA-approved drug.
- Clinical research may be supported but not clinical trials.
NIAID plans to hold a pre-application informational webinar for this FOA. Details about webinar registration will be updated at the FOA link below. Participation in the webinar is not required to submit an application.
Antiviral Drug Discovery (AViDD) Centers for Pathogens of Pandemic Concern (U19 Clinical Trial Not Allowed) RFA-AI-21-050. National Institutes of Allergy and Infectious Diseases Application Due Date: 22 October 2021.
