Newton 001 Development of new GPCRs interacting drugs to treat inflammatory diseases

The overwhelming systemic inflammatory response triggered by acute infection (sepsis) and its progression into septic shock can lead to progressive organ dysfunction. This condition has a 70-90% mortality rate and is a major public health problem both the UK and Brazil. In Brazil there has been a dramatic increase in the number of sepsis-associated deaths (9.8% in 2002 to 16.5% in 2010). A major challenge in the treatment of sepsis-induced cardiovascular collapse is the fact that
it is not responsive to standard vasopressor and inotropic treatments. This situation is aggravated in populations where healthcare provision is not readily accessible, either for socio-economical or geographical reasons, leading to exacerbation of the underlying infection. The proposed work intends to exploit recent knowledge of the ability of drugs to bias responses from cell surface receptors to particular intracellular signalling pathways in order to develop inotropic and vasopressor treatments that are effective in sepsis.

Inflammatory diseases are a complex and heterogeneous group of diseases that affect more than 10% of the population. These diseases are a major cause of morbidity and mortality and are an important socioeconomic problem. Despite scientific and technological advances of recent decades, the current treatment options for inflammatory diseases are still limited. There is therefore a clear medical need to develop better pharmacological tools to keep inflammation under control. A good example of this is sepsis, classically defined as an overwhelming systemic inflammatory response triggered by an acute infection that leads to progressive organ dysfunction and death. The major problem with the treatment of the cardiovascular collapse that occurs in sepsis is the fact that it is not responsive to standard vasopressor and inotropic treatments. Our partners in Brazil recently demonstrated that this pharmacological hypo-responsiveness is due to adrenoceptor internalization and desensitization and suggested that biased agonists that stimulate G-protein signalling without effect on receptor internalization would be an efficient strategy for the development of new therapies.
The Cell Signalling Research Group (CSRG) led by Professor Steve Hill at the University of Nottingham (UoN) has a world-class reputation for the study of GPCRs, particularly for the investigation of ligand-receptor interactions, intracellular signalling, allosterism and receptor dimerization. The UoN also has considerable strength in medicinal chemistry led by Professors Barrie Kellam within The Division of Medicinal Chemistry and Structural Biology (DMCSB) of the School of Pharmacy. CSRG and DMCSB scientists have recently completed a joint drug discovery programme that has developed highly selective be1-adrenoceptor antagonists. The aim of this proposal is to develop an intercontinental collaborative consortium to develop novel biased agonists for the beta-1-adrenoceptor.

N/A