Can residence time offer a useful strategy to target agonist drugs for sustained GPCR responses?

Abstract

Residence time describes the how long a ligand is bound to its target, and is attracting interest in drug discovery as a potential means of improving clinical efficacy by increasing target coverage. This concept, as originally applied to antagonists, is more complicated for G-protein-coupled receptor (GPCR) agonists because of the transiency of receptor responses (via desensitization and internalization). However, in some cases sustained GPCR agonist responses have been observed, with evidence consistent with a role for slow binding kinetics. We propose a model to explain our understanding of how residence time and rebinding might influence sustained signaling by internalized receptors. We also highlight the anticipated benefit for drug discovery of fully understanding and exploiting these phenomena to target desirable receptor response profiles selectively.

Structure-Activity Relationships of the Sustained Effects of Adenosine A2A Receptor Agonists Driven by Slow Dissociation Kinetics

“…This suggests that certain ligand-specific properties can regulate duration of action after washing and confer sustained agonism. Similar phenomena have been observed for a growing number of GPCR agonists, although it is often challenging to determine the precise mechanisms through which this occurs (Hothersall et al, 2016). …”

“…The most straightforward explanation for sustained wash-resistant agonist responses is slow ligand dissociation kinetics (Hothersall et al, 2016). We therefore assessed agonist off-rates using the real-time GloSensor cAMP assay by monitoring antagonist mediated reversal of pre-established agonist responses.…”

“…Our findings are also consistent with previous observations that the irreversibly binding A2A agonist DITC-APEC can exert sustained activation in intact tissue that cannot be reversed by antagonist (Niiya et al, 1993). Clearly, persistent agonist responses will be facilitated by a low level of receptor regulatory processes that normally serve to dampen receptor responsiveness (Hothersall et al, 2016). Indeed, a lack of desensitization and internalization as was previously demonstrated for A2A (Zezula and Freissmuth, 2008), although other investigators have observed agonist-driven loss of A2A responsiveness, which points toward an important role for cellular context (Chern et al, 1993, 1995; Palmer et al, 1994).…”

“…Therefore, for A2A drug discovery programs it is critical to increase our understanding of the temporal response profiles of drug candidates and the mechanisms through which long/short duration of action can occur. Optimizing ligand binding kinetics has been advocated as a valuable strategy for achieving appropriate duration of action and target coverage (Copeland et al, 2006; Guo et al, 2014; Hothersall et al, 2016). Specifically, slow A2A agonist dissociation kinetics have been cited as a potential mechanism to achieve a desirable clinical response for topically applied drugs (Mantell et al, 2010).…”

The Added Value of Assessing Ligand–Receptor Binding Kinetics in Drug Discovery

“…A number of clues come from recent studies examining the subcellular localization of fluorescently tagged agonists and receptors. As observed, an internalized ligand− receptor binary complex with continued ligand binding, i.e., long receptor residence time, can still trigger sustained signaling from cytosolic compartments (see the review 11 and references therein for detailed information). Thus, studying the kinetics of ligand−receptor interaction adds new facets to the understanding of the molecular basis of drug action.…”