Neuropeptide S receptor: understanding the molecular bases of ligand binding and receptor activation
Abstract:
G Protein Coupled Receptors (GPCRs) are the largest family of membrane proteins representing the target for ~25% of marketed drugs. Class A GPCRs comprise validated targets for central nervous system (CNS), cardiovascular, gastro-intestinal, respiratory, and oncologic disease treatment. About one third of these receptors are activated by endogenous peptides.
Neuropeptide S (NPS) is a 20-amino acid peptide activating a formerly orphan GPCR154 - now NPS receptor (NPSR), which activation promotes cellular excitability via Gq and Gs signalling. Despite NPS expression being localised to a few brain areas, NPSR-mediated effects are widely distributed in CNS regions associated with stress response, memory, and arousal regulation. Studies in both rodents and humans suggest that NPSR antagonists show potential to attenuate drug-seeking behaviours, while NPSR agonists represent innovative non-sedating anxiolytics with memory enhancement effects. Notably, NPSR anxiolytic effects are mediated exclusively by Gq signalling, thus suggesting the search for Gq-biased NPSR agonists as a promising strategy for innovative CNS drugs development. Despite the huge interest and intense drug discovery efforts over the last two decades, NPSR remains an elusive target for which no high-affinity drug-like clinical candidates are available yet. There is therefore a compelling need for the development of small-molecule NPSR agonists that can help elucidate uncharted aspects of the NPS/NPSR system pharmacology and of drug-like antagonists that can contribute to its therapeutic validation as drug target for CNS diseases.
By harnessing our joint expertise in molecular modelling, synthetic chemistry, biochemistry, and in vitro pharmacology, this project aims at unleashing NPSR therapeutic potential via a thorough investigation of its ligand binding and activation mechanisms. The proposed research plan will provide novel assays and protocols for NPSR ligand characterisation that will provide insights on peptide and non-peptide binder SARs, receptor activation, and G protein biased signalling. We therefore believe that the results this research will yield will usher in a new era of structure-based design of novel NPSR modulators with improved efficacy and drug-like properties, a challenge that has remained unmet in the last two decades.
The application of the computational and experimental techniques, protocols, and concepts that will be developed by a collaborative effort of scientist with complementary expertise will extend beyond NPSR and pave the way for extending our multi-disciplinary approach to other GPCRs. Hence, the proposed plan and the tools it will create have the potential to speed up the disclosure of novel drug targets, contribute to the development of novel therapeutic strategies to treat CNS diseases, and ultimately increase the number of safer and more effective drugs approved.
Neuropeptide S (NPS) is a 20-amino acid peptide activating a formerly orphan GPCR154 - now NPS receptor (NPSR), which activation promotes cellular excitability via Gq and Gs signalling. Despite NPS expression being localised to a few brain areas, NPSR-mediated effects are widely distributed in CNS regions associated with stress response, memory, and arousal regulation. Studies in both rodents and humans suggest that NPSR antagonists show potential to attenuate drug-seeking behaviours, while NPSR agonists represent innovative non-sedating anxiolytics with memory enhancement effects. Notably, NPSR anxiolytic effects are mediated exclusively by Gq signalling, thus suggesting the search for Gq-biased NPSR agonists as a promising strategy for innovative CNS drugs development. Despite the huge interest and intense drug discovery efforts over the last two decades, NPSR remains an elusive target for which no high-affinity drug-like clinical candidates are available yet. There is therefore a compelling need for the development of small-molecule NPSR agonists that can help elucidate uncharted aspects of the NPS/NPSR system pharmacology and of drug-like antagonists that can contribute to its therapeutic validation as drug target for CNS diseases.
By harnessing our joint expertise in molecular modelling, synthetic chemistry, biochemistry, and in vitro pharmacology, this project aims at unleashing NPSR therapeutic potential via a thorough investigation of its ligand binding and activation mechanisms. The proposed research plan will provide novel assays and protocols for NPSR ligand characterisation that will provide insights on peptide and non-peptide binder SARs, receptor activation, and G protein biased signalling. We therefore believe that the results this research will yield will usher in a new era of structure-based design of novel NPSR modulators with improved efficacy and drug-like properties, a challenge that has remained unmet in the last two decades.
The application of the computational and experimental techniques, protocols, and concepts that will be developed by a collaborative effort of scientist with complementary expertise will extend beyond NPSR and pave the way for extending our multi-disciplinary approach to other GPCRs. Hence, the proposed plan and the tools it will create have the potential to speed up the disclosure of novel drug targets, contribute to the development of novel therapeutic strategies to treat CNS diseases, and ultimately increase the number of safer and more effective drugs approved.
Dettagli progetto:
Referente scientifico: Ciancetta Antonella
Fonte di finanziamento: Bando PRIN 2022
Data di avvio: 05/10/2023
Data di fine: 05/10/2025
Contributo MUR: 93.981 €
Co-finanziamento UniFe: 3.932 €
Partner:
- Università degli Studi di FERRARA (capofila)
- Università degli Studi di PADOVA