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Papers of the Week

Papers: 23 Jul 2022 - 29 Jul 2022

2022 Aug 02

Proc Natl Acad Sci U S A



An analgesic peptide H-20 attenuates chronic pain via the PD-1 pathway with few adverse effects.


Zhao L, Luo H, Ma Y, Zhu S, Wu Y, Lu M, Yao X, Liu X, Chen G
Proc Natl Acad Sci U S A. 2022 Aug 02; 119(31):e2204114119.
PMID: 35878019.


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 naïve 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.