PIs: Professor Christiane Berger-Schaffitzel, Professor Adrian Mulholland, Dr Christopher Woods, and Richard Pitts (Oracle for Research)
We aim to determine, at atomic resolution, the structural basis and functional consequences of small molecule binding to a novel site we discovered in FFAR1/GPR40, a G-protein coupled receptor (GPCR) and key drug target for treating long COVID. To this end, we will select from a synthetic nanobody library high-affinity binders of FFAR1 using Ribosome Display in vitro selection and evolution (Schaffitzel et al., 1999). By protein engineering, we will create megabodies (Uchanski et al., 2021) and deploy these engineered megabodies to unlock the high-resolution cryo-EM structure of megabody-bound FFAR1 in complex with our agonist candidates, which we identified in a previous drug discovery programme. By biophysical and mutational studies as well as molecular modelling, binding of our small molecule agonist drug candidates to a novel site in FFAR1 has been confirmed. Moreover, we already completed, with several candidates, preclinical studies up to oral efficacy in mice. The cryo-EM structural characterisation of the drug-bound FFAR1 complex will be combined with molecular dynamics simulations of agonist binding, powered by Oracle cloud. The objective of this project is to provide essential atomic detail, as a basis for translating our agonist drug candidates into the clinic, ultimately for treating lung fibrosis (Gagnon et al., 2018) a hallmark of long-COVID.