An analgesic peptide H-20 attenuates chronic pain via the PD-1 pathway with few adverse effects.
Proc Natl Acad Sci U S A
; 119(31): e2204114119, 2022 08 02.
Article
em En
| MEDLINE
| ID: mdl-35878019
ABSTRACT
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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Peptídeos
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Dor Crônica
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Receptor de Morte Celular Programada 1
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Analgésicos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article