PD-1: A New Candidate Target for Analgesic Peptide Design

Chronic pain is a common health problem in humans. The unique properties and valuable clinical applications of analgesic peptides make them attractive pharmacotherapy options for pain control. Numerous targets for pain modulation processes are currently known, including opioid receptors, transient receptor potential (TRP) channels, voltage-gated ion channels, neuronal nicotinic receptors, and neurotensin receptors. However, these targets are not able to address the development needs of peptide-based drugs. Recent studies revealed that programmed cell death 1 (PD-1) is widely expressed in the dorsal root ganglia (DRG), spinal cord, and cerebral cortex. PD-1 signaling in neurons is involved in the regulation of neuronal excitability, synaptic transmission, and synaptic plasticity. PD-1 is able to silence nociceptive neurons upon activation. Consistently, Pd1 deficiency or blockade increases the pain sensitivity in naïve mice. PD-1 agonists, including PD-L1 and H-20, evoke Src homology 2 domain-containing tyrosine phosphatase-1 (SHP-1) phosphorylation, modulate neuronal excitability, and attenuate acute and chronic pain with minimal opioid-related adverse effects, suggesting a superior therapeutic index and a sound strategy for the development novel nonopioid analgesics. In addition, PD-1 signaling in non-neuronal cells could alleviate chronic pain by regulating neuroinflammation. Here, we review the potential and challenges of PD-1 as a candidate target for the development of analgesic peptides. Perspective This review paper aims to review recent advances in research on PD-1 in the domain of pain interference, explore how to obtain more promising PD-1 receptor-targeting analgesic peptides based on PD-L1 and analgesic peptide H-20 for relieving pathological pain, and offer potential optimization strategies for follow-up work of H-20.