E. B. Hershberg Award: Taming Inflammation by Tuning Purinergic Signaling DOI
Kenneth A. Jacobson

Accounts of Chemical Research, Journal Year: 2025, Volume and Issue: unknown

Published: March 5, 2025

ConspectusThe author presents his personal story from early contributions in purinergic receptor research to present-day structure-guided medicinal chemistry. Modulating signaling (encompassing pyrimidine nucleotides as well) and other nucleoside targets with small molecules is fruitful for identifying new directions therapeutic intervention. Purinergic encompasses four adenosine receptors, eight P2Y receptors that respond various extracellular nucleotides, trimeric P2X mainly ATP. Each organ tissue the body expresses some combination of this family cell-surface along enzymes transporters form, degrade, process native nucleotide agonists. The system responds physiological stress an organ, example by increasing energy supply or decreasing demand. are widespread on immune cells, such activation boosts response when where it needed, repel infection. In contrast, which activated later process─as stress-elevated ATP hydrolyzed locally ectonucleotidases─tend put brakes inflammation can be used correct imbalance pro- versus anti-inflammatory signals, chronic pain. Hypoxia activates immunosuppressive adenosine-A2A axis, originally formulated Sitkovsky, suppresses tumor microenvironment make a cancer more aggressive. Conversely, effects agonists have numerous applications. Modulators also show promise treating pain, metabolic disorders, inflammation. Thus, control harnessed wide range conditions, neurodegeneration autoimmune inflammatory diseases ischemia brain heart.The author's receiving American Chemical Society's top award chemistry 2023 provides opportunity summarize these developments their origins empirical probing receptor-ligand structure-activity relationship (SAR) current structure-based approaches, including conformational selectivity toward signaling. work each target began either before soon after was cloned, initial focus academic exercise use organic develop SAR target. Jacobson lab has introduced chemical probes 17 well associated regulators. Furthermore, surprisingly, conformationally constrained analogues designed inhibit non-purinergic selectively, opioid serotonin monoamine transporters. Only did applications pharmacological become apparent. largely enabled biological making definitive tool compounds available. Five laboratory (four derivatives) currently clinical trials (autoimmune liver conditions) acute (stroke, traumatic injury) conditions.

Language: Английский

Cryo-EM structures of adenosine receptor A3AR bound to selective agonists DOI Creative Commons
Hongmin Cai, Shimeng Guo, Youwei Xu

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: April 16, 2024

Abstract The adenosine A 3 receptor (A AR), a key member of the G protein-coupled family, is promising therapeutic target for inflammatory and cancerous conditions. selective AR agonists, CF101 CF102, are clinically significant, yet their recognition mechanisms remained elusive. Here we report cryogenic electron microscopy structures full-length human bound to CF102 with heterotrimeric i protein in complex at 3.3-3.2 Å resolution. These agonists reside orthosteric pocket, forming conserved interactions via adenine moieties, while 3-iodobenzyl groups exhibit distinct orientations. Functional assays reveal critical role extracellular loop AR’s ligand selectivity activation. Key mutations, including His 3.37 , Ser 5.42 6.52 unique sub-pocket AR, significantly impact Comparative analysis inactive 2A structure highlights activation mechanism. Our findings provide comprehensive insights into molecular signaling paving way designing subtype-selective ligands.

Language: Английский

Citations

21
E. B. Hershberg Award: Taming Inflammation by Tuning Purinergic Signaling DOI
Kenneth A. Jacobson

Accounts of Chemical Research, Journal Year: 2025, Volume and Issue: unknown

Published: March 5, 2025

ConspectusThe author presents his personal story from early contributions in purinergic receptor research to present-day structure-guided medicinal chemistry. Modulating signaling (encompassing pyrimidine nucleotides as well) and other nucleoside targets with small molecules is fruitful for identifying new directions therapeutic intervention. Purinergic encompasses four adenosine receptors, eight P2Y receptors that respond various extracellular nucleotides, trimeric P2X mainly ATP. Each organ tissue the body expresses some combination of this family cell-surface along enzymes transporters form, degrade, process native nucleotide agonists. The system responds physiological stress an organ, example by increasing energy supply or decreasing demand. are widespread on immune cells, such activation boosts response when where it needed, repel infection. In contrast, which activated later process─as stress-elevated ATP hydrolyzed locally ectonucleotidases─tend put brakes inflammation can be used correct imbalance pro- versus anti-inflammatory signals, chronic pain. Hypoxia activates immunosuppressive adenosine-A2A axis, originally formulated Sitkovsky, suppresses tumor microenvironment make a cancer more aggressive. Conversely, effects agonists have numerous applications. Modulators also show promise treating pain, metabolic disorders, inflammation. Thus, control harnessed wide range conditions, neurodegeneration autoimmune inflammatory diseases ischemia brain heart.The author's receiving American Chemical Society's top award chemistry 2023 provides opportunity summarize these developments their origins empirical probing receptor-ligand structure-activity relationship (SAR) current structure-based approaches, including conformational selectivity toward signaling. work each target began either before soon after was cloned, initial focus academic exercise use organic develop SAR target. Jacobson lab has introduced chemical probes 17 well associated regulators. Furthermore, surprisingly, conformationally constrained analogues designed inhibit non-purinergic selectively, opioid serotonin monoamine transporters. Only did applications pharmacological become apparent. largely enabled biological making definitive tool compounds available. Five laboratory (four derivatives) currently clinical trials (autoimmune liver conditions) acute (stroke, traumatic injury) conditions.

Language: Английский

Citations

0