Development of novel host-centric antiviral agents suitable for multi-host species

About the Project

A few years ago, we made a groundbreaking discovery of a plant-derived antiviral molecule, thapsigargin (TG), that is highly effective against major human and animal respiratory viruses: IAV, coronaviruses (including SARS-CoV-2) and respiratory syncytial virus (Al-Beltagi et al., 2021a; Al-Beltagi et al., 2021b; Goulding et al., 2020). Our findings that TG is a host-centric antiviral have been later corroborated by other groups (Shaban et al., 2022; Shaban et al., 2021). TG, a sesquiterpene lactone, is an irreversible inhibitor of the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) pump whose inhibition prevents the replenishment of the ER Ca2+ pool, triggering (i) store operated calcium entry (SOCE) and (ii) ER stress and the unfolded protein response (UPR). Both processes culminate in a cellular antiviral state that blocks virus replication at multiple stages of virus life cycle.

Inspired by TG, we recently created a library (> 180) of second-generation semi-synthetic antivirals that can be structurally categorised into different compound families, exhibiting improved drug-like properties and safety whilst retaining antiviral efficacy against a range human and veterinary RNA viruses. A major problem of all existing virus-targeting antivirals, such as baloxavir, is the emergence of virus resistance which rapidly reduces their usefulness (Hayden et al., 2018; Leung et al., 2024; Uehara et al., 2020). The huge advantage of host-centric antivirals are much less susceptible to virus resistance since virus mutations cannot readily overcome its dependency on host cell functions.

The aims of this PhD project is the in vitro and in vivo Drug Metabolism and Pharmacokinetics (DMPK) development of novel host-centric antiviral candidates.

PhD student involved in this project will have a unique opportunity to learn skills and knowledge highly sought after by both pharmaceutical industry and academia, including Biopharmaceutics, Pharmacokinetics, Pharmacodynamics, Drug Delivery, Preclinical Models and Virology.

For informal inquiries please contact Dr Pavel Gershkovich: pavel.gershkovich@nottingham.ac.uk

Funding Notes

Applications are invited from self-funded students. This project has secured substantial external funding for experimental work, but tuition fees or stipend are not covered.