E. B. Hershberg Award: Taming Inflammation by Tuning Purinergic Signaling

The author presents his personal story from early contributions in purinergic receptor research to present-day structure-guided medicinal chemistry. Modulating purinergic signaling (encompassing pyrimidine nucleotides as well) and other nucleoside targets with small molecules is fruitful for identifying new directions for therapeutic intervention. Purinergic signaling encompasses four adenosine receptors, eight P2Y receptors that respond to various extracellular nucleotides, and trimeric P2X receptors that respond mainly to ATP. Each organ and tissue in the body expresses some combination of this family of cell-surface receptors, along with the enzymes and transporters that form, degrade, and process the native nucleoside and nucleotide agonists. The purinergic signaling system responds to physiological stress to an organ, for example by increasing the energy supply or decreasing the energy demand. The receptors are widespread on immune cells, such that P2Y and P2X receptor activation boosts the immune response when and where it is needed, for example to repel infection. In contrast, the adenosine receptors, which are activated later in the process─as stress-elevated ATP is hydrolyzed locally to adenosine by ectonucleotidases─tend to put the brakes on inflammation and can be used to correct an imbalance in pro- versus anti-inflammatory signals, such as in chronic pain. Hypoxia activates the immunosuppressive extracellular adenosine-A_2A adenosine receptor axis, as originally formulated by Sitkovsky, which suppresses the immune response in the tumor microenvironment to make a cancer more aggressive. Conversely, the anti-inflammatory effects of adenosine receptor agonists have numerous therapeutic applications. Modulators of P2Y receptors, which respond to extracellular nucleotides, also show promise for treating chronic pain, metabolic disorders, and inflammation. Thus, control of this signaling system can be harnessed for treating a wide range of conditions, from cancer and neurodegeneration to autoimmune inflammatory diseases to ischemia of the brain or heart. The author's receiving the American Chemical Society's top award for medicinal chemistry in 2023 provides an opportunity to summarize these developments from their origins in empirical probing of receptor-ligand structure-activity relationship (SAR) to the current structure-based approaches, including conformational control of selectivity toward purinergic signaling. The work on each target receptor began either before or soon after it was cloned, and the initial focus was an academic exercise to use organic chemistry to develop a SAR for each target. The Jacobson lab has introduced chemical probes for 17 of the purinergic receptors as well as for associated regulators. Furthermore, surprisingly, some of the conformationally constrained nucleoside analogues can be designed to inhibit non-purinergic targets selectively, such as opioid and serotonin receptors and monoamine transporters. Only later did therapeutic applications of these pharmacological probes become apparent. Thus, the medicinal chemistry has largely enabled biological research on purinergic signaling by making definitive tool compounds available. Five compounds from the Jacobson laboratory (four adenosine derivatives) are currently in clinical trials for various chronic (autoimmune inflammatory and liver conditions) and acute (stroke, traumatic brain injury) conditions.