ArticleProceedings of the National Academy of Sciences of the United States of America2014
Targeting the minor pocket of C5aR for the rational design of an oral allosteric inhibitor for inflammatory and neuropathic pain relief.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 77 citations in OpenAlex.
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- The Pleiotropic Effect of Complement C5a-C5aR1 Pathway in Diseases: From Immune Regulation to Targeted Therapy.International journal of molecular sciences · 2025Review
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- Reducing IgG accumulation via neonatal Fc receptor (FcRn) blockade relieves neuropathic pain.Brain, behavior, and immunity · 2025Article
- Schwann cell C5aR1 co-opts inflammasome NLRP1 to sustain pain in a mouse model of endometriosis.Nature communications · 2024Article
- The value of protein allostery in rational anticancer drug design: an update.Expert opinion on drug discovery · 2024Review
- Active immunotherapy for C5a-mediated inflammation using adjuvant-free self-assembled peptide nanofibers.Acta biomaterialia · 2024Article
- The complement system: a potential target for the comorbidity of chronic pain and depression.The Korean journal of pain · 2024Article
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- C5aR1 signaling triggers lung immunopathology in COVID-19 through neutrophil extracellular traps.The Journal of clinical investigation · 2023Article
- Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands.International journal of molecular sciences · 2023Review
- A Structure-Based Allosteric Modulator Design Paradigm.Health data science · 2023Review
- Emerging Approaches for the Management of Chemotherapy-Induced Peripheral Neuropathy (CIPN): Therapeutic Potential of the C5a/C5aR Axis.Pain and therapy · 2022Review
- Shared Genetic Regulatory Networks Contribute to Neuropathic and Inflammatory Pain: Multi-Omics Systems Analysis.Biomolecules · 2022Article
- Association of Pain with Plasma C5a in Patients with Neuromyelitis Optica Spectrum Disorders During Remission.Neuropsychiatric disease and treatment · 2022Article
- Guhong Injection Prevents Ischemic Stroke-Induced Neuro-Inflammation and Neuron Loss Through Regulation of C5ar1.Frontiers in pharmacology · 2022Article
- Emerging Role of C5 Complement Pathway in Peripheral Neuropathies: Current Treatments and Future Perspectives.Biomedicines · 2021Review
- Binding Mode Exploration of B1 Receptor Antagonists' by the Use of Molecular Dynamics and Docking Simulation-How Different Target Engagement Can Determine Different Biological Effects.International journal of molecular sciences · 2020Article
- Novel Analgesics with Peripheral Targets.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2020Review
Corrections and comments
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Authors and funding
21 authors at 6 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Chronic pain resulting from inflammatory and neuropathic disorders causes considerable economic and social burden. Pharmacological therapies currently available for certain types of pain are only partially effective and may cause severe adverse side effects. The C5a anaphylatoxin acting on its cognate G protein-coupled receptor (GPCR), C5aR, is a potent pronociceptive mediator in several models of inflammatory and neuropathic pain. Although there has long been interest in the identification of C5aR inhibitors, their development has been complicated, as for many peptidomimetic drugs, mostly by poor drug-like properties. Herein, we report the de novo design of a potent and selective C5aR noncompetitive allosteric inhibitor, DF2593A, guided by the hypothesis that an allosteric site, the "minor pocket," previously characterized in CXC chemokine receptors-1 and -2, is functionally conserved in the GPCR class. In vitro, DF2593A potently inhibited C5a-induced migration of human and rodent neutrophils. In vivo, oral administration of DF2593A effectively reduced mechanical hyperalgesia in several models of acute and chronic inflammatory and neuropathic pain, without any apparent side effects. Mechanical hyperalgesia after spared nerve injury was also reduced in C5aR(-/-) mice compared with WT mice. Furthermore, treatment of C5aR(-/-) mice with DF2593A did not produce any further antinociceptive effect compared with C5aR(-/-) mice treated with vehicle. The successful medicinal chemistry strategy confirms that a conserved minor pocket is amenable for the rational design of selective inhibitors and the pharmacological results support that the allosteric blockade of the C5aR represents a highly promising therapeutic approach to control chronic inflammatory and neuropathic pain.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.