Rapidly transitioning from in silico hits to leads on ‘undruggable’ pain targets

Opioid addiction is an ongoing crisis in the US. Researchers have identified a key regulator that shapes analgesic and aversive outputs of kappa opioid receptor signalling, finding lead inhibitors of this previously ‘undruggable’ target class – the Regulators of G protein Signalling (RGS proteins) – to help re-establish non-addictive kappa agonists into the analgesic space. This article summarises their work to-date, including a high-throughput fluorescence assay of GTPase acceleration for rapid hit-to-lead refinement.

Though recently overshadowed by the COVID-19 pandemic, the US continues to suffer from an opioid addiction crisis. In 2017, more than 2.1 million Americans were diagnosed with opioid use disorder1 and the rate of drug overdose deaths due to synthetic opioids like fentanyl increased by 56 percent from 2019 to 2020.2 There is a link between misuse of prescription opioid analgesics and illicit heroin use; it is estimated that seven out of 10 people who used heroin in the US have also misused prescription opioids.1

Opioid addiction results from modulation of the endogenous opioid system composed of three main receptors: the mu opioid receptor, the kappa opioid receptor and the delta opioid receptor. Opioid receptors are seven-transmembrane (7TM) receptors coupled to a heterotrimeric G protein underneath. Upon receptor activation, guanosine diphosphate (GDP) is exchanged for guanosine triphosphate (GTP) in the G-alpha subunit, leading to its dissociation from other parts of the heterotrimeric G protein in order to…