Molecular dissection of viral genomes for future antiviral treatments

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.