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Molecular dissection of viral genomes for future antiviral treatments

Project description

Towards new antiviral drugs

There is a high unmet medical need for antiviral drugs. Funded by the European Research Council, the MEDICATE project aims to address this issue by focusing on the identification of new transmembrane viral proteins. Some viruses express such proteins, which play vital roles in virus replication or virulence. MEDICATE researchers will identify viral sequences that encode transmembrane proteins and explore their potential as drug targets. Specifically, they will investigate putative viral ion channels and possibly use them as targets through drug repurposing. Overall, the project is expected to drive a novel path in antiviral drug discovery.

Objective

Viruses are obligate pathogens with massive impact on global health. Nearly all currently marketed antiviral drugs target viral enzymes. We hypothesize that hitherto unrecognized virus-encoded transmembrane proteins may prove valuable as pharmaceutical targets.

Through a systematic dissection of viral genomes (WP1) we will identify potential transmembrane segments in a defined workflow. We will predict their function in silico (WP2) as being either (A) internalizing transmembrane proteins or (B) ion channels. Segments showing promising transmembrane and/or internalization motifs will be expressed, functionally characterized and evaluated in proof-of-modality assays (WP3). The newly identified internalizing proteins may transfer a molecular Trojan horse, a toxin payload, into infected cells, which will be tested with a generic fusion-toxin protein (Mode A), while the potential viral ion channels (viroporins) will be tested for their ability to mediate a current via formation of ion pores (Mode B). In WP4, the internalizing transmembrane proteins passing the WP1-3 attrition will be utilized for initial drug discovery and fusion-toxin protein design. Through co-internalization with the viral transmembrane protein, the toxins may prevent long-term pathologies by eradicating the virus. The novel viroporins will be screened for inhibition using ion channel drugs regulatory approved for other purposes. This ensures fast access to the market through drug repurposing, allowing for prevention and treatment of acute virus pathology.

This project on new ground entails high risk, yet also creates opportunities of enormous gain, considering the huge unmet medical needs for effective and specific antiviral therapeutics. However, the biggest gain is the potential for ground-breaking discoveries regarding virally encoded transmembrane proteins, thereby bridging basic virology and molecular pharmacology with structural biology and early drug discovery in a highly innovative manner.

Host institution

KOBENHAVNS UNIVERSITET
Net EU contribution
€ 2 420 301,00
Address
NORREGADE 10
1165 Kobenhavn
Denmark

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Region
Danmark Hovedstaden Byen København
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 2 420 301,00

Beneficiaries (1)