Viruses intimately rely upon host signalling and cellular machinery to support their survival and replication. Phosphoinositide 3-kinases (PI3K) are a ubiquitous family of proteins which coordinate signalling pathways that promote programmes of cell survival, macromolecule synthesis, metabolism, and endocytosis. PI3K components are frequently involved in cancer aetiology and have been investigated for chemotherapy research. Various studies have also demonstrated a link between host PI3K signalling and viruses, with pathway components extensively activated or upregulated during infection with viruses like herpes simplex virus type 1 (HSV-1).
Antiviral resistance is a significant concern for many clinically available treatments, which are primarily direct-acting. The use of host-acting antivirals could reduce dependence on drugs for which resistance is increasing. Repurposing existing drugs provides further benefits with lower costs and pre-existing characterisation of safety. PI3K inhibitors have an extensive history as chemotherapies, and have demonstrated antiviral efficacy in vitro against a wide range of viruses, including HSV-1, Epstein-Barr virus, SARS-CoV-2, influenza, etc. The benefits of these inhibitors may extend beyond combatting antiviral resistance, helping provide broad-spectrum protection against diverse lineages of viruses.
In this study, we investigated the efficacy of PI3K inhibitors originally developed for chemotherapy against HSV-1. Two of the nine compounds assayed showed antiviral activity at <10μM, one of which showed enhanced activity in combination with the commercial antiviral Acyclovir, for which resistance is increasing. The treatment potential of a synergistic combination of direct-and host-acting antivirals is enhanced by the reduced potential for antiviral resistance and host toxicity, leading to increasing development of combination antivirals.
This work demonstrates the therapeutic potential of PI3K inhibitors for herpes viral infections, and the enhanced treatment potential of drug combinations. These could help provide improved treatment efficacy for resistant viruses, as well as new treatments for novel/emerging viruses.