Viruses are obligatory pathogens that significantly impact global health. Most current antiviral drugs target viral enzymes. We propose that previously unrecognized viral transmembrane proteins could serve as valuable pharmaceutical targets.
By dissecting viral genomes, we aim to identify potential transmembrane segments through a defined workflow. We will predict their function in silico (WP1) as either (A) internalizing transmembrane proteins or (B) ion channels. Promising segments will be expressed, functionally characterized, and evaluated in proof-of-modality assays (WP2). The internalizing proteins will be tested for their ability to transfer a molecular Trojan horse, a toxin payload, into cells using a universal fusion-toxin protein (Modality A). Potential viral ion channels (viroporins) will be assessed for their ability to mediate a current (Modality B).
In WP3, fusion toxin proteins will be produced for internalizing targets that pass WP1-2 attrition. These toxins, co-internalized with viral targets, will prevent long-term pathologies by eradicating the virus. Viroporins will be screened for inhibition using ion channel drugs already approved for other purposes, ensuring fast market access through drug repurposing and expediting the pipeline for acute viral illness prevention and treatment.
Finally, in WP4, the identified viral target/drug pairs will be tested for antiviral efficacy using virus-infected human organoids and/or discarded human organs.
This innovative project, while high-risk, holds the potential for significant gains given the unmet medical need for effective antiviral therapeutics. The greatest prospect lies in the potential for groundbreaking discoveries regarding virally encoded transmembrane proteins, bridging basic virology, molecular pharmacology, structural biology, and early drug discovery.
