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Drug discovery is a multidisciplonary effort. AVITHRAPID brings together a team of highly skilled experts in molecular modeling, structural biology, assay development, toxicity profiling, antiviral drug discovery, animal model testing, and clinical trials. Several partners have successfully worked on the discovery of novel antiviral substances. In addition, one pharma partner has identified a small molecule drug against Zika virus that is ready to enter clinical trials.

The unique portfolio of substances ranges from validated hits to pre-clinical candidates with proven in vivo efficacy. To further develop and validate this portfolion the AVITHRAPID consortium will work together in 8 Work Packages (WPs) which operate as an integrated pre-clinical drug discovery value chain.

Lead Participant: Università degli Studi di Napoli Federico II  – Italy

Objectives

The objective of Work Package 1 is the optimization of lead chemical series acting against selected targets and displaying the potential to function as broad-spectrum antiviral agents to be transferred to Work Package 2 and tested in different in vivo models.

Description of work

The WP tasks will involve synthetic and computational chemistry, assay development, biological evaluation (in vitro and cell-based screening on several viruses) and X-ray structural analysis. Subsequent compound selection, based on potency against the isolated target, cell-based antiviral activity and physicochemical profile, will allow to shortlist a small set of compounds to be engaged in Work Package 2. 

Task 1: Development of biochemical assay for innovative broad-spectrum viral target: Aim of this task is establishing a FRET-based biochemical assay for the screening of a panel of compounds obtained through a virtual screening campaign.

Task 2: SARS-CoV-2 Helicase Inhibitor Development: Helicase is a primary antiviral target due to its essential function in the viral replication of large variety of pathogens. The starting point of this task is a series of small molecules with nM potency in the enzymatic assay for the NTPase and helicase assays and μM activity in the SARS-CoV-2 antiviral assay and no cytotoxicity (CC50 > 300 μM).

Task 3: SARS-CoV-2 PLpro Enzyme Inhibitor development: This task will focus on the optimization of fourteen validated hits that have been identified in a screen at the European Lead Factory.

Task 4: Nsp3 macrodomain inhibitors as broad-spectrum antivirals development: Macrodomains are present in diverse viruses such as coronaviruses, chikungunya virus (CHIKV) or hepatitis-E virus (HEV) and carry an enzymatic activity that removes ADP-ribosyl groups added to viral or host proteins by host PARPs, thereby counteracting the host immune response.

Task 5: Development of DDX3X host factor inhibitors as broad-spectrum antivirals: DDX3X is a DEAD-Box helicase and is a host factor hijacked by several families of RNA viruses. The inhibition or silencing of this host enzyme was demonstrated to be efficacious in vitro with several viruses such as HIV-1, WNV, DENV, ZIKV, JEV, HCV etc. Consequently, DDX3X inhibitors are an optimal candidate for the identification of a broad-spectrum antiviral and a potentially antiviral for Disease X.

Task 6: Peptide-porphyrin conjugates development: Peptide-porphyrin conjugates are extremely broad-spectrum antiviral drugs able to penetrate the brain and placenta, therefore capable of protecting the central nervous system and fetuses from the action of viruses. They owe their broad spectrum of activity to the peculiar target in the viral structure: the lipid envelope.

Task 7: Broad-spectrum anti-viral potential of the compounds on risk group 4 viruses: The broad-spectrum anti-viral potential of the compounds developed in tasks 1-6 will be evaluated also on risk group 4 (RG4) viruses which are listed as priority diseases by the World Health Organization (WHO) and for which therapeutics are still lacking. The top-ranking molecules will be selected and tested against different RG4 viruses, including Ebola, Nipah, Hendra, Lassa, using virus-cell-based assays.

Lead Participant: Institut national de recherche pour l’agriculture, l’alimentation et l’environnement – France

Objectives

– Obtain regulatory project authorizations from ethical and ministerial committees

– Define the toxicity of the selected compounds (maximum 10) in vitro in the model animal and their mode of administration

– Follow the metabolism and degradation in biological fluids

– To investigate the antiviral potential of selected compounds with viruses like coronavirus and Zika virus in animal models.

– Proof of concept: to evaluate the therapeutic efficacy of the best selected compounds (maximum 5) on viral development and their immune impact.

– Set up a bank of healthy and infectious tissues/biological fluids available to all partners.

Description of work

Task 1: General safety and pharmacokinetic assays: The nonclinical safety assessment for marketing approval of a pharmaceutical includes general toxicity studies and toxicokinetic studies. Safety experiments in non-infected animals will be performed exploiting a safety profiling platform.

Task 2: Proof of concept: in vivo toxicity of different antiviral candidates selected in vitro:
– In vivo
trials and collection of samples (sera and tissues):
Depending on the results obtained in WP1 and on the galenic excavations realized and compatible with the living, we will test at most 10 antiviral promising compounds.
– In vivo Toxicity: This step is preliminary to allow a proof of concept before moving to a field study. The objective of this part is thus to allow to test in vivo, for a pathogen selected in vitro responsible for respiratory diseases like coronaviruses for example
– Tracking the antiviral: PK/PD studies on biological samples such as serum will be performed to monitor the active compounds and/or metabolic drift of these compounds.

Task 3: Physiopathology of the viral agents (SARS-CoV-2 and Zika virus models):
Among the emerging viruses inducing sanitary crises, two viral models have been selected for this project, coronaviruses including the SARS-CoV-2 virus and the Zika virus and will be tested in vivo on different animal models.
– Virus preparation for experimental installations
A reference D614G strain (BetaCoV/France/IDF0571/2020; GISAID EpiCoV platform Accession ID EPI_ISL_411218), and the variant that will be dominant in Europe at the time of the analysis will be used. The Zika virus sample to be used throughout the studies is a clinical isolate obtained from a febrile case in Pernambuco State, Brazil (ZIKVBR, gene bank ref. number KX197192).
– In vivo models: We will use the K18-hACE2 mouse (B6.Cg-Tg(K18-ACE2)2Prlmn/J line) and golden hamster models which are complementary for the development of the physiopathology of SARS-Cov-2 and to optimize the efficacy of new drug candidates.

Task 4: Proof of concept: Efficacity of antiviral compounds against Zika and SARS-CoV-2:
After validation of the infectious model, different compounds will be tested in vivo (5 maximum).

 

Lead Participant: Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani-Istituto di ricovero e cura a carattere scientifico – Italy

Objective

To provide safety and eventually efficacy data on treatment of patients affected with Zika virus infection.

Description of work

The Clinical Study (AVITHRAPID-TRIAL) will be designed according to current clinical epidemiological data coming from ZIKV endemic countries.

Task 1: Set up of the clinical trial management committee (CTMC): The Committee will be made up of the Work Package leader, a delegate of the Sponsor, by a data manager, by the statistician and by the heads of the experimental units.

Task 2: Verification of the capacity of the experimental units and implementation of any supplementary/corrective actions: On the basis of the objectives and methodologies defined for the Clinical Trial, the capabilities of the clinical units selected for conducting the study will be verified, and the operational feasibility of the trial within the units will be verified.

Task 3: Check of the ethical issues of the clinical trial and definition of the management policy for them: The Ethical Issues Support Unit (EIU) of the project will be involved in the evaluation of the methodologies and objectives of the Clinical Trial and will produce an initial guideline document and recommendations for drafting the study protocol.

Task 4: Definition and writing of the synopsis and protocol: The writing of the trial Synopsis and protocol will be distributed and verified by the CTMC among all competent subjects.

Task 5: Preparatory actions and start of the clinical trial: The preparatory actions include: submission of the Clinical Trial on the European CTIS platform (Clinical Trials Information System) and follow up until clearance.

Task 6: Conduct the clinical trial: The study will be conducted as defined in the previous tasks and in accordance with all applicable regulations.

Task 7: Data verification and analysis: The trial data will be verified throughout the duration of the study and the final cleaning will make it possible to release the database for analysis, after the data manager has made a data management report available.

Task 8: Writing and publication of the final report: The final report will be approved by the CTMC after it has been reviewed and approved by the ethics unit.

Lead Participant: Dompé farmaceutici SpA – Italy

Objectives

To perform advanced sequencing analysis to identify new potential targets to be modelled and used for structure-based in silico.
– To support the identification of potential active molecules (repurposed drugs or new chemical entities) to be validated in Work Package 1 and characterized in Work Package 2.
– To integrate various sources of information produced in the other packages as well as collected from external sources to apply machine learning methods for the selection of the most promising compounds for experimental screening and their physical-chemical characterization.

Description of work

WP4 will support the other projects at different stages. The deployment of these activities on state-of-the-art supercomputing centers will allow the computational steps to be accelerated.

Task 1:  NGS data analysis of viral genomes: To apply computational tools to identify new protein targets, particularly for emerging viruses or new variants of existing viruses by evaluating viral genomes

Task 2: In silico data analysis of protein targets: In this task, in silico methods such as homology modelling, using known 3D models as templates, will be applied to model selected protein target structures.

Task 3: Artificial Intelligence model for compound scoring: Artificial Intelligence (AI) methods will be applied to develop a score that will be used for different purposes depending on the stage in which the compound is used

Task 4: Support Hit to series and Hit to Lead phases: With the objective of speeding up the compound optimization phases in WP1 the 3D models of proteins obtained from the Task 4.2 or already available, will be used to develop Molecular Docking models based on single or multiple conformations of proteins (Ensemble docking) obtained from Molecular dynamics simulations or experimentally determined.

Task 5 – Deployment and efficient execution of bioinformatic pipelines: This task will support the execution of the pipelines that are built in other tasks and make sure the deployment and execution workflows are as efficient and performant as possible.

Lead Participant: First Health Pharmaceuticals B.V. – Netherlands

Objectives

– To support the progression of active compounds throughout the project toward in vivo Proof of Concept by identifying and developing adequate formulations to overcome potential issues such as low solubility or low bioavailability.
– To identify the most adequate innovative formulation to ensure that the antiviral achieves the infected organs and cell populations.

Description of work  

The aim is to support the development of the compounds identified by the other Work Packages by improving their distribution, delivery and performance in vivo.

Task 1: Milk-derived Extracellular Vesicles (EVs): EVs are micro- and nanosized structures enclosed in a phospholipidic double-layer membrane that are produced by all cell types, that transport a complex cargo of proteins, antigens, lipids, metabolites, RNAs, and DNA fragments and are released in the extracellular environment, reaching both close and distant cells.

Task 2: Conjugation of molecules with peptides: The discovery and development of powerful cell-penetrating peptides able to enter the cells or to traverse the blood-brain and blood-placental barriers are used to transport drugs including antiviral and vaccines.

Task 3: Liposomes for formulating compounds or for the loading of EV: Liposomes are microscopic hollow spheres, typically made of bilayers of natural or semisynthetic phospholipids and/or cholesterol, known to overcome low solubility limitations, to extend the circulation time of the encapsulated drugs in the blood stream, to reduce drug clearance, and to decrease off-targets side effects.

Task 4: Estimation of drug loading and experimental validation: Methodologies to study and quantify drug-lipid interaction will be used to optimize the interaction between drugs and lipid vesicles.

Task 5: Other routes of administration: Pre-formulation of compound for the inhaling route through mEVs is being applying the spray drying technology as proper for mEVs stabilization to preserve their function and enable the loaded drug delivery through inhaling and oral routes.

Lead Participant: Chelonia SA – Switzerland

Objectives

This WP comprises the different steps, stages, messages and tools to be used to widely spread the progress and results of the project and to exploit them. Objectives of this WP are:
– Raise awareness in collaboration with WP1 – amongst different audiences about the opportunities repurposing brings in for patients with unmet clinical needs and inform and help build credibility among all relevant stakeholders about the infrastructure the project will develop.
– Support all WPs in their communication needs, facilitating consistency and alignment with the overall communication strategy, plans and materials to achieve maximum impact.
– Ensure that the project is sustainable and exploitable after the project duration, including the creation of a marketplace of providers that can offer their services through the AVITHRAPID platform.

Both internal and external Communication and Dissemination activities internally and externally to the Consortium are planned and dealt with to ensure the awareness of the project results and to spread out promptly the utilisation of the project results, beyond the project partners and time-frame.

Description of work

Plan a set of activities and tools to increase the visibility and awareness of the project results and support their impact, by promoting dissemination and communication of the innovative deliverables developed in the project and by adopting a model to exploit the results obtained.

Tasks 1: Communication and dissemination strategy and tactical plans: Produce a communication and dissemination strategy with clear objectives and key messages, outlining profiled audiences and recommending an appropriate channel mix.

Task 2 Communication tools and support to Work Packages: Develop communication tools to support the project needs and maximise dissemination

Task 3 Business planning: Design a sustainability plan to ensure exploitation of project results and achievement of long-term impacts. A consortium agreement together with a business plan will guide the associated impetus for identifying, prioritizing and protecting the project strategic IP for possible formal patent filings.

Lead Participant: Fraunhofer Gesellschaft zur Förderung der angewandten Forschung

Objectives

This Work Package includes the responsability for the operational data management and FAIR data assessment of the consortium. The members of this group will be recruited from all the Work Packages and will be the key contacts for all data-related matters.

Description of work

Task 1: Define guidelines for data management across the project: We will establish guidelines for data governance, management and quality to be applied across i) the operational activities of other WPs, and ii) the downstream analyses of aggregated data addressing priority scientific questions.

Task 2: Define and identify tools which can be implemented across the projects for operational data management needs, and which meet defined standards: We will create software specifications, review existing installed tools and identify tools from within the project or externally which meet the operational needs of the projects, and which are compliant with the data quality guidelines.

Task 3: Establish IT Infrastructure to support data aggregation and sharing: Data and workflows generated for data analysis within the project would be deposited in GDPR-compliant format within existing infrastructures such as GitHub, Zenodo, and other domain-specific repositories.

Task 4: Common standards, tools, interoperability etc. when working with collaborators: In this task, we will establish a common technical framework to promote efficient cooperation with collaborators or subcontractors to facilitate sharing of data and knowledge across the global research community.

Lead Participant: Fraunhofer Gesellschaft zur Förderung der angewandten Forschung

Objectives

– Optimally coordinate project activities, promoting strategic direction, alignment and achievement of its goals.
– Set-up a management structure that ensures efficient operational execution of the project
– Ensure high quality project implementation according to the work plan and within budgeted costs
– Promote effective internal communication, knowledge management and work dynamics between participants to help drive the whole Consortium as a team towards successful completion of the project.

Description of work

Task 1: Day to day management: We will provide support to the scientific coordination and the overall management structure in: (1) Liaison with the EC; (2) Work plan control and update, schedule control, implementation of corrective actions; (3) Support the project coordination in decision making and linkage of project components; (4) Support WPs in day to day management and implementation of tasks promoting synergies & efficiency; (5) Set up and manage the SF, Policy Board and Ethics Board; (6) Support General Assembly in meeting organisation (logistics, minutes, etc.).

Task 2 Reporting and administration: To comply with reporting and financial procedures, this activity will deal with Financial management, Periodic Reporting, Contractual and other legal issues related to the project.

Task 3: Risk management: We will identify, assess and follow-up threats and opportunities likely to affect the project performance following a bottom-up approach.

Task 4: Internal communication: Set up specific tools for internal communication across the hub and knowledge management will be an early priority.