SAFER was established in 2017 with training and research activities initiated at the beginning of 2018 with the enrolment of five ESRs working towards the following scientific goals:
1) Provide a rationale for the design of safer drugs by uncovering molecular mechanisms for functional selectivity at the serotonin 5-HT2A receptor.
2) Identify ligands with therapeutically favorable 5-HT2A signaling profile(s).
3) Develop a public GPCR ligand database including functionally selective agonists
Background:
Serotonin, or 5-hydroxytryptamine (5-HT), is a neurotransmitter that gives feelings of wellbeing and happiness, regulates mood, appetite, and sleep and also has cognitive functions, including memory and learning. The serotonergic system is very complex, comprising 14 different receptor subtypes: 13 G-protein-coupled receptors (GPCRs) and one ligand-gated ion channel. SAFER has a particular focus on the 5-HT2A receptor subtype, which is a validated drug target in the treatment of schizophrenia and other psychoses, cluster headaches and glaucoma. At UCPH, numerous agonists targeting this receptor have been developed including the most selective 5-HT2A receptor agonist reported to date, which is now being used to investigate the effects of selective activation of the 5-HT2A receptor in various animal models. Furthermore, at UCPH a PET-ligand ([11C]Cimbi-36) was taken “from bench to bedside” – i.e. from medicinal chemistry development to clinical applications.
Scientific problem:
There is accumulating clinical evidence that 5-HT2A receptor agonists can relieve the suffering of treatment-resistant depressive patients and anxiety in terminal cancer patients. However, their therapeutic mode of action is currently very poorly understood due to the unselective nature of the current drugs. Furthermore, the impact of selectively activating different signaling pathways of the 5-HT2A receptor is unknown, as such functionally selective ligands remains to be discovered.
SAFER solution:
1) Through a detailed investigation of the binding mode of know agonist to the 5-HT2Ar several hypothesizes have been developed and tested by SAFER. This process has been aided by the recent disclosure of several Cryo-EM structures of the 5-HT2AR in complex with various ligands.
2) SAFER has identified functionally Selective Agonists For the 5-HT2A Serotonin Receptor through an iterative. In particular, a ligand with a strong preference for the Gq-pathway will be further investigated to elucidate the downstream effects of this destint pharmacological profile
3) The GPCRdb (
https://gpcrdb.org/(se abrirá en una nueva ventana)) has been extending to include a comprehensive coverage of literature data on biased agonists. This database is available with an intuitive and fully searchable format to provide reachers a easy entry into this comprehensive data set.
Impact:
In this European Industrial Doctorates project, the public private partnership collaboration is important and crucial for the success of the research and training in the program. The results obtained, in particular through the two ESRs employed by SARomics have had an impact on the business opportunities for the company. The setup of a platform for biostructural work on GPCRs and experience working with GPCR receptors will facilitate future business opportunities in the field. Similarly, the extensive knowledge in computational chemistry problems and possibilities in this specific field will provide basis for commercialization of this knowledge. Concrete, the collaborative publication in Nature will be used in marketing of company capabilities. Thus, through the last years SARomics has expanded their activities with new employees.
The collaboration with Enamine was been hampered by two ESRs leaving the project, however, the remaining ESR, Database Development, has successfully transferred knowledge to the company in the GPCR field. This may be used in creation of business opportunities towards new selective compounds and compound libraries to be commercialized. SAFER will provide the first tools for dissection of 5-HT2A signaling and apply them to reveal the therapeutic mechanisms of 5-HT2A agonists. This will open up clinical opportunities beyond this 3-year program. As the most important part of this program SAFER will provide training for 5 ESRs as the next generation of researchers in this important field of health science.
