Allostery-driven G protein selectivity in the adenosine A1 receptor

Overview

The A1R is a high-value drug target but is linked to serious cardiovascular side effects because it activates multiple G proteins. BnOCPA preferentially activates Gob, thus conferring pain relief in vivo without cardiovascular side effects. Here we propose a rational approach to designing G protein-selective A1R agonists.

Objectives

Objective 1. Determine the molecular mechanism by which BnOCPA displays Gob selectivity

Objective 2. Identify characteristic features in the ligand-receptor interaction dynamics responsible for G protein selective agonists

Objective 3. Design a high affinity, high efficacy BnOCPA-based agonist with selectivity for Gob

Impact Statement

The realisation that agonists may exhibit bias towards individual GPCR-mediated signalling cascades has reinvigorated GPCR pharmacology. This implies that the large number of previously undruggable receptors can be successfully exploited for therapeutics. The A1R is a primary example. The discoveries we will make in this ambitious project have the potential to extend to other ‘undruggable’ GPCRs, so enabling their potential future exploitation. The ability to specifically tailor an agonist to activate an individual G protein-mediated pathway can help unlock future production of novel therapies that lead to increased long-term life expectancy and improved quality of life; both are key national priorities for the UK. Our primary outlet will be our links with Astra Zeneca and Sosei Heptares, both UK-based companies with global reach and proven ability to translate new research.

Outputs 

Based on previous joint work, we anticipate at least 5 interdisciplinary, high-impact manuscripts to be published in open access journals during the project with dissemination of data at conferences and via preprints beginning after 6 months.

Our research showcases UK strengths in GPCR pharmacology that can together unlock potential new classes of therapies that will have future impact on public health. This should both excite and involve the public as key stakeholders. To ensure this, we plan for our work to be presented at engagement events (Coventry and Cambridge science festivals), and at the Big Bang UK Young Scientists & Engineers Fair (~70k attendees aged 7-19). Our results will be divulged at dedicated social events such as the Pint of Science Festival and Research Café sessions at Coventry.