Unlocking Free Fatty Acid Receptor 1 (FFAR1): Allosteric Modulation and Extracellular Ligand Binding for Long COVID Therapies
Lead Research Organisation:
University of Bristol
Department Name: Biochemistry
Abstract
Idiopathic pulmonary fibrosis (IPF) is a debilitating and currently incurable disease. The incidence of IPF is rising due to a significant
number of COVID-19 survivors developing lung fibrosis. Additionally, millions of people worldwide suffer from long COVID, putting
them at risk of developing lung fibrosis (LF). Unfortunately, no preventive measures or effective therapies exist for these lung
complications, and current post-COVID LF treatments are inadequate. The Free Fatty Acid Receptor 1 (FFAR1) has emerged as a
potential target for treating long COVID-related LF. Activating FFAR1 has shown promise in inhibiting fibrosis progression. However,
past attempts to target FFAR1 with drugs have been hindered by hepatotoxicity. Recent research has uncovered a novel extracellular
binding site on FFAR1, offering a potential avenue for drug development without previous toxicity concerns. Still, the exact nature of
ligands binding to this site remains unknown.
This project aims to enhance our understanding of FFAR1's extracellular site and its interaction with promising allosteric agonists
through a combination of X-ray crystallography and cutting-edge methods like cryo-electron microscopy and molecular dynamics
simulations. The research aims to elucidate the structural dynamics of FFAR1 in complex with these novel agonists, providing insights
crucial for drug design. The study also introduces innovative methods for crystallizing FFAR1, potentially revolutionizing structure-based
drug discovery for G protein-coupled receptors (GPCRs) and membrane proteins.
In conclusion, this project seeks to uncover the molecular mechanisms behind FFAR1 activation, ultimately contributing to the
development of safer and more effective therapies for post-COVID LF and other diseases associated with FFAR1. It bridges critical
knowledge gaps in GPCR pharmacology and structure and holds the potential to transform drug discovery and our understanding of
FFAR1's role in health and disease.
number of COVID-19 survivors developing lung fibrosis. Additionally, millions of people worldwide suffer from long COVID, putting
them at risk of developing lung fibrosis (LF). Unfortunately, no preventive measures or effective therapies exist for these lung
complications, and current post-COVID LF treatments are inadequate. The Free Fatty Acid Receptor 1 (FFAR1) has emerged as a
potential target for treating long COVID-related LF. Activating FFAR1 has shown promise in inhibiting fibrosis progression. However,
past attempts to target FFAR1 with drugs have been hindered by hepatotoxicity. Recent research has uncovered a novel extracellular
binding site on FFAR1, offering a potential avenue for drug development without previous toxicity concerns. Still, the exact nature of
ligands binding to this site remains unknown.
This project aims to enhance our understanding of FFAR1's extracellular site and its interaction with promising allosteric agonists
through a combination of X-ray crystallography and cutting-edge methods like cryo-electron microscopy and molecular dynamics
simulations. The research aims to elucidate the structural dynamics of FFAR1 in complex with these novel agonists, providing insights
crucial for drug design. The study also introduces innovative methods for crystallizing FFAR1, potentially revolutionizing structure-based
drug discovery for G protein-coupled receptors (GPCRs) and membrane proteins.
In conclusion, this project seeks to uncover the molecular mechanisms behind FFAR1 activation, ultimately contributing to the
development of safer and more effective therapies for post-COVID LF and other diseases associated with FFAR1. It bridges critical
knowledge gaps in GPCR pharmacology and structure and holds the potential to transform drug discovery and our understanding of
FFAR1's role in health and disease.
Publications
Deniaud A
(2024)
Sample Preparation for Electron Cryo-Microscopy of Macromolecular Machines.
in Advances in experimental medicine and biology
| Description | A novel extracellular pocket and oxazole-based agonists binding to the pocket. |
| Exploitation Route | We work with Halo Therapeutics Ltd and Novo Nordisk to secure invest and to drive this project forward. |
| Sectors | Healthcare Pharmaceuticals and Medical Biotechnology |
| Description | Based on our preliminary results we started to reach out to industry to secure investment to further develop our lead candidate agonists for FFAR1. We talk to Novo Nordisk, and via the golden ticket award receive monthly mentoring by their R&D department. We currently host Mr Mihai Vasile from the Vollmer team at University of Exeter Vollmer in our laboratory for a 3-months placement. He learns insect cell expression and purification of membrane proteins, including G-protein coupled receptors. |
| First Year Of Impact | 2025 |
| Sector | Healthcare,Pharmaceuticals and Medical Biotechnology |
| Impact Types | Economic |
| Description | Appointed Committee member of the Wellcome Trust Career Development Award Interview Committee (2022-2024) |
| Geographic Reach | National |
| Policy Influence Type | Participation in a guidance/advisory committee |
| Description | Appointed Monitor EC Horizon 2020, FET open programme (2021-2025) |
| Geographic Reach | Europe |
| Policy Influence Type | Contribution to a national consultation/review |
| Description | Appointed member of Oversight committee for 1.2 GHz NMR in the UK (2024-today) |
| Geographic Reach | National |
| Policy Influence Type | Contribution to a national consultation/review |
| Description | Appointed member of the iNEXT Horizon 2020 - Discovery Advisory Panel (2020-2024) |
| Geographic Reach | Europe |
| Policy Influence Type | Participation in a guidance/advisory committee |
| Impact | iNEXT brings together structural biology facilities for X-rays, NMR, cryo-EM and macromolecular biophysics, and aims to make them accessible to new user communities, to develop the methods further through joined research efforts, and to offer better integration between scientific fields and within the field of structural biology through scientific meetings, practical courses, and training workshops. A major aim of iNEXT-Discovery is providing access to users from the European Union and all associated countries, to all participating facilities. Importantly, it aims to not only make available state of the art instruments, but also make available to all users expert support, to help non-experts answer exciting scientific questions. |
| URL | https://inext-discovery.eu/network/inext-d/networking |
| Description | Chair of the reviewer panel of the NCCR Antiresist |
| Geographic Reach | National |
| Policy Influence Type | Participation in a guidance/advisory committee |
| URL | https://www.nccr-antiresist.ch/ |
| Description | Co-Chair of the review panel of the NCCR 'Bio-inspired Materials' |
| Geographic Reach | National |
| Policy Influence Type | Participation in a guidance/advisory committee |
| URL | https://www.bioinspired-materials.ch/en/ |
| Description | Member of the evaluation panel for the 6th NCCR series of SNSF (National Centre of Competence in Research), Switzerland |
| Geographic Reach | National |
| Policy Influence Type | Contribution to a national consultation/review |
| URL | https://www.news.admin.ch/en/newnsb/JEYzIEzRw1QFKXIpHWlxC |
| Description | Wittenstein Foundation, Reviewer for Joint professorship University of Hohenheim & Frauenhofer Institute, Germany |
| Geographic Reach | Local/Municipal/Regional |
| Policy Influence Type | Contribution to a national consultation/review |
| Description | Collaboration with Dr Andrew Quigley on agonist bound GPCR structure (drug development) |
| Organisation | Diamond Light Source |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | We established sample production and drug binding |
| Collaborator Contribution | We collaborate with the membrane protein laboratory, the Rosalind Franklin Institute and eBIC to solve the structure of an agonist bound G-protein coupled receptor (GPCR). We have optimized detergents, tested detergent-alternatives and started lipid cubic phase crystallisation, generation of novel nanobodies binding the GPCR and feezing grids for Cryo-EM in collaboration with the scientists at the Diamond light source. |
| Impact | BBSRC BrisEngBio Proof of Concept award. Megabody in vitro selection and engineering for cryo-EM structure analysis of FFAR1-bound lung fibrosis drugs to treat long COVID, |
| Start Year | 2022 |
| Description | Collaboration with Dr Robin Corey on molecular dynamics simulations of drug candidate-bound FFAR1 |
| Organisation | University of Bristol |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Production of FFAR1 with drug candidate bound and cryo-EM structure |
| Collaborator Contribution | molecular dynamics simulations on FFAR1 allosteric activation by drug candidate |
| Impact | no outcomes yet |
| Start Year | 2025 |
| Description | collaboration with Dr Chris Tate, LMB Cambridge, on Cryo-EM of drug-candidate bound FFAR1 |
| Organisation | Medical Research Council (MRC) |
| Department | MRC Laboratory of Molecular Biology (LMB) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Production of drug candidate-bound FFAR1, characterisation and single particle cryo-EM |
| Collaborator Contribution | Expertise on cryo-EM sample preparation and structural analysis of GPCRs |
| Impact | no outputs yet |
| Start Year | 2025 |
| Description | Bristol Biodesign Institute Innovation Training Showcase |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Industry/Business |
| Results and Impact | Bristol Biodesign Institute Innovation Training Showcase at ScienceCreates, Bristol, 20th June 2024 , Dr Konrad Hus gave a pitch to investors entitled: "ADDovenom - Novel Solution for Snakebite Crisis" |
| Year(s) Of Engagement Activity | 2024 |
| Description | British-Swiss Synbio Summit, London, UK |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Industry/Business |
| Results and Impact | Discussed international collaboration and the future impact of AI on research and development. |
| Year(s) Of Engagement Activity | 2025 |
| Description | Presentation at Board of Trustees Meeting, University of Bristol |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Other audiences |
| Results and Impact | I presented the project on Friday 31. January 2025 at the Board of Trustees meeting at University of Bristol (https://www.bristol.ac.uk/university/governance/university-governance/board-of-trustees/). The project was selected as an exemplary project for Engineering Biology at the University. |
| Year(s) Of Engagement Activity | 2025 |
| Description | Talk at School of Cellular Medicine and Microbiology, Univ. of Bristol |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Postgraduate students |
| Results and Impact | Presented our SARS-CoV-2 spike protein structure and ongoing work in the laboratory. |
| Year(s) Of Engagement Activity | 2025 |
| Description | UK Japan Engineering Biology Workshop, London UK, networking panelist |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Postgraduate students |
| Results and Impact | Participated in a panel discussion abut the importance of research collaborations and team work in the presence of ca 120 participants |
| Year(s) Of Engagement Activity | 2025 |
| Description | University of Leicester, Biochemistry Seminar |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Postgraduate students |
| Results and Impact | Presented ongoing and past research in the laboratory to ca 40 PhD students, Postdocs and PIs. |
| Year(s) Of Engagement Activity | 2026 |