Project description
2C enterovirus protein as a candidate target for broad-spectrum antivirals
The enteroviruses (EV) are represented by hundreds of human pathogens, including poliovirus, coxsackieviruses, EV-A71, EV-D68 and rhinoviruses. The sheer number of these viruses makes the vaccination against all of these impossible and calls for effective broad-spectrum antivirals. The non-structural 2C viral protein is an attractive target for the development of antivirals due to its high level of sequence conservation. The EU-funded EV-2C project will determine the high-resolution structure of the 2C and inhibitor/ligand complexes by cryo-electron microscopy and characterise the interactions of 2C viral and host proteins within ex-vivo and in situ replication organelles. Understanding the organisation of 2C within replication organelles and its high-resolution structure will serve as a template for structure-based anti-enteroviral drug design.
Objective
The enterovirus (EV) genus comprises many important human pathogens including poliovirus, coxsackieviruses, EV-A71, EV-D68 and rhinoviruses. These viruses are responsible for a wide array of diseases ranging from mild to life-threatening, such as neonatal sepsis and paralysis. There are hundreds of enteroviruses, and vaccination to all of these is not a viable option. As such, there is an urgent requirement for effective broad-spectrum antivirals.
Enterovirus genomes comprise a positive-sense ssRNA genome which encodes four structural proteins (VP1--4) and seven non-structural proteins (2A--C, 3A--D). The non-structural proteins 2B, 2C and 3A cooperatively hijack host cell proteins and alter host cell membranes and lipid homeostasis to generate membranous replication organelles, which serve as platforms for genome replication and virion morphogenesis.
The 2C protein is a particularly attractive target for the development of antivirals due to its high level of sequence conservation. 2C is an AAA+ ATPase with many proposed functions within the virus lifecycle including helicase activity, reorganisation of cellular membranes and encapsidation. Several structurally disparate drugs target 2C on the basis that resistance mutations map to this protein; however, the molecular basis of their effect on 2C is not understood.
This project has two main objectives:
1. Determine the high-resolution structure of the functional hexameric 2C and inhibitor/ligand complexes by cryo-electron microscopy.
2. Use cryo-electron tomography to characterise the interactions 2C makes with viral and host proteins within ex-vivo and in situ replication organelles.
Understanding the organisation of 2C within replication organelles will shed new light on its role in the enterovirus life cycle, and the high-resolution structure of 2C will serve as a long sought-after search template for structure-based drug design of urgently-needed anti-enteroviral drugs.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- medical and health sciences basic medicine medicinal chemistry
- natural sciences biological sciences biochemistry biomolecules proteins
- natural sciences physical sciences optics microscopy electron microscopy
- medical and health sciences basic medicine physiology homeostasis
- medical and health sciences basic medicine pharmacology and pharmacy pharmaceutical drugs antivirals
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Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions
MAIN PROGRAMME
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H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
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Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
MSCA-IF-EF-ST - Standard EF
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Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) H2020-MSCA-IF-2018
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
3584 CS Utrecht
Netherlands
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.