Molecular Genetics Section, National Institute of Dental and Craniofacial Research/NIH, 35 Convent Drive, Bethesda, MD 20892, USA.
Division of Pre-Clinical Investigation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
Sci Transl Med. 2019 Jul 10;11(500). doi: 10.1126/scitranslmed.aav5464.
There is a major clinical need for new therapies for the treatment of chronic itch. Many of the molecular components involved in itch neurotransmission are known, including the neuropeptide NPPB, a transmitter required for normal itch responses to multiple pruritogens in mice. Here, we investigated the potential for a novel strategy for the treatment of itch that involves the inhibition of the NPPB receptor NPR1 (natriuretic peptide receptor 1). Because there are no available effective human NPR1 (hNPR1) antagonists, we performed a high-throughput cell-based screen and identified 15 small-molecule hNPR1 inhibitors. Using in vitro assays, we demonstrated that these compounds specifically inhibit hNPR1 and murine NPR1 (mNPR1). In vivo, NPR1 antagonism attenuated behavioral responses to both acute itch- and chronic itch-challenged mice. Together, our results suggest that inhibiting NPR1 might be an effective strategy for treating acute and chronic itch.
治疗慢性瘙痒症的新疗法具有重要的临床需求。许多涉及瘙痒递质传递的分子成分已被知晓，包括 NPPB 神经肽，它是小鼠对多种瘙痒原正常瘙痒反应所必需的递质。在此，我们研究了一种新的瘙痒治疗策略的潜力，该策略涉及 NPPB 受体 NPR1（利钠肽受体 1）的抑制。由于没有有效的人类 NPR1（hNPR1）拮抗剂，我们进行了高通量基于细胞的筛选，鉴定出 15 种小分子 hNPR1 抑制剂。使用体外测定，我们证明这些化合物特异性抑制 hNPR1 和鼠 NPR1（mNPR1）。在体内，NPR1 拮抗作用减弱了对急性瘙痒和慢性瘙痒挑战的小鼠的行为反应。总之，我们的结果表明，抑制 NPR1 可能是治疗急性和慢性瘙痒的有效策略。
