Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 119, Issue 31, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2204114119
Keywords
chronic pain; programmed cell death protein 1; analgesic; Src homology 2 domain-containing tyrosine phosphatase 1; dorsal root ganglion
Categories
Funding
- National Natural Science Foundation of China [82101302, 32070998]
- National Key Research and Development Program of China [2017YFA0104704]
- Key Research and Development Program (Social Development) of Jiangsu Province [BE2020667]
- Foundation of Jiangsu Province 333 Project High-Level Talents [BRA2020076]
- Six Talent Peaks Project in Jiangsu Province [2017-SWYY-056]
- Jiangsu Province Innovation And Entrepreneurship Training Program for College Students [202110304030Z]
- Nantong Civic Science and Technology Project of China [JC2021113]
- Priority Academic Program Development of Jiangsu Higher Education Institutions
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The lack of effective and safe analgesics for chronic pain management has long been a health issue. Analgesic peptides, without opioid-related adverse effects, have recently shown promise for pain treatment. This study discovers that the peptide H-20 binds to PD-1, reduces nociceptive signals, and displays effective analgesia in preclinical pain models, making it a promising candidate drug for chronic pain treatment.
The lack of effective and safe analgesics for chronic pain management has been a health problem associated with people's livelihoods for many years. Analgesic peptides have recently shown significant therapeutic potential, as they are devoid of opioid-related adverse effects. Programmed cell death protein 1 (PD-1) is widely expressed in neurons. Activation of PD-1 by PD-L1 modulates neuronal excitability and evokes significant analgesic effects, making it a promising target for pain treatment. However, the research and development of small molecule analgesic peptides targeting PD-1 have not been reported. Here, we screened the peptide H-20 using high-throughput screening. The in vitro data demonstrated that H-20 binds to PD-1 with micromolar affinity, evokes Src homology 2 domain-containing tyrosine phosphatase 1 (SHP-1) phosphorylation, and diminishes nociceptive signals in dorsal root ganglion (DRG) neurons. Preemptive treatment with H-20 effectively attenuates perceived pain in naive WT mice. Spinal H-20 administration displayed effective and longer-lasting analgesia in multiple preclinical pain models with a reduction in or absence of tolerance, abuse liability, constipation, itch, and motor coordination impairment. In summary, our findings reveal that H-20 is a promising candidate drug that ameliorates chronic pain in the clinic.
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