BOS-318 is a cell-permeable, potent, and highly selective inhibitor of furin (IC50=1.9nM)[1-2]. BOS-318 is applicable for research in cystic fibrosis (CF) lung disease and can serve as an adjunctive therapy to CFTR modulators such as ETI[3-4].
In vitro, treatment of differentiated cystic fibrosis human bronchial epithelial cells (CF HBECs) with BOS-318 (0.3µM) for 2 or 48 hours significantly inhibited epithelial sodium channel (ENaC)-mediated sodium absorption. A 2- or 48-hour pretreatment of CF HBECs with BOS-318 (0.3µM), followed by stimulation with neutrophil elastase (NE; 2.5µg/mL) or CF sputum supernatant. BOS-318 protected ENaC from activation by NE. Treatment of CuFi-1 cells with BOS-318 (0.001–1µM) for 72 hours conferred dose-dependent protection against Pseudomonas aeruginosa exotoxin A (PEA; 500ng/mL)-mediated cytotoxicity[5]. In BRAF-mutated human melanoma cell lines (A375M6 and M21), a 24-hour treatment with BOS-318 (5nM) reduced the expression of TGFβ1 and phosphorylated SMAD2. When combined with pirfenidone (8.1mM), BOS-318 synergistically increased p21 expression and elevated the proportion of cells entering late apoptosis[6].
In vivo, in a mouse model of acute lung injury induced by Pseudomonas aeruginosa (PA103) or exotoxin A (Exo-A), a single administration of BOS-318 (5mM; i.p.; 200µL; and 0.874mM; intratracheal; 50µL) 1 hour prior to infection significantly improved survival at 96 hours post-infection, attenuated hypothermia and body weight loss, reduced protein and inflammatory cytokine levels in bronchoalveolar lavage fluid (BALF), and accelerated bacterial clearance[7]. In adult C57BL/6 mice, a single oral dose of BOS-318 (10mg/kg) administered 24 hours before electrophysiological experiments. BOS-318 significantly inhibited furin activity in tissues and prevented the PAR1 agonist TFLLR-NH2-induced potentiation of neuromuscular transmission[8].
References:
[1] Douglas LEJ, Reihill JA, Martin SL. BOS-318 treatment enhances elexacaftor-tezacaftor-ivacaftor-mediated improvements in airway hydration and mucociliary transport. ERJ Open Res. 2025 Feb 25;11(1):00445-2024.
[2] Nayak D, Wasmuth EV, Olsen SK. Clearing the air: Uniquely engaging furin as an approach to cystic fibrosis therapy. Cell Chem Biol. 2022 Jun 16;29(6):927-929.
[3] Ducrocq GP, Anselmi L, Stella SL Jr, et al. Inhibition and potentiation of the exercise pressor reflex by pharmacological modulation of TRPC6 in male rats. J Physiol. 2025 Sep;603(18):5027-5052.
[4] Ridgway H, Orbell JD, Matsoukas MT, et al. W254 in furin functions as a molecular gate promoting anti-viral drug binding: Elucidation of putative drug tunneling and docking by non-equilibrium molecular dynamics. Comput Struct Biotechnol J. 2023 Sep 9;21:4589-4612.
[5] Douglas LEJ, Reihill JA, Ho MWY, et al. A highly selective, cell-permeable furin inhibitor BOS-318 rescues key features of cystic fibrosis airway disease. Cell Chem Biol. 2022 Jun 16;29(6):947-957.e8.
[6] Marchese M, La Regina G, Amato R, et al. The unexplored mechanism of antitumoral effect of pirfenidone in melanoma cells. Sci Rep. 2025 Aug 1;15(1):28071.
[7] Bernard O, Kwon M, Looney MR, et al. Furin Inhibition Protects Against Acute Lung Injury in a Mouse Model of Pseudomonas Aeruginosa Infection. Am J Respir Cell Mol Biol. 2026 Feb 15:aanag024.
[8] Molchanova, A.I., Shepelev, E.I., Gaydukov, A.E. PAR1-Mediated Retrograde Action of Brain-Derived Neurotrophic Factor and Its Prodomain in Mature Mouse Motor Synapses is Provided by Furin Activity. Neurochem J. 2025; 19: 717–727.
BOS-318是一种具有细胞渗透性的、高效且高选择性的弗林蛋白酶（furin；IC50=1.9nM）抑制剂[1-2]。BOS-318可用于囊性纤维化（CF）肺病的研究，并可作为CFTR调节剂疗法（如ETI）的辅助治疗手段[3-4]。
在体外，BOS-318（0.3μM）处理分化的囊性纤维化人气道上皮细胞（CF HBECs）2小时或48小时，可显著抑制上皮钠通道（ENaC）介导的钠离子吸收。BOS-318（0.3μM）预处理CF HBECs 2小时或48小时，随后以中性粒细胞弹性蛋白酶（NE；2.5μg/mL）或CF痰液上清刺激。BOS-318可保护ENaC免受NE的激活。BOS-318（0.001–1μM）处理CuFi-1细胞72小时，可剂量依赖性地保护细胞免受铜绿假单胞菌外毒素A（PEA；500ng/mL）介导的细胞毒性[5]。BOS-318（5nM）处理BRAF突变的人黑色素瘤细胞系（A375M6和M21）24小时。BOS-318能够降低TGFβ1和磷酸化SMAD2的表达；当与吡非尼酮（8.1mM）联合处理时，BOS-318可协同增加p21表达，提高进入晚期凋亡的细胞比例[6]。
在体内，BOS-318在感染前1小时单次给药（5mM；腹腔注射；200μL；及0.874mM；气道内给药；50μL）于铜绿假单胞菌（PA103）或外毒素A（Exo-A）诱导的小鼠急性肺损伤模型中，可显著提高感染后96小时的生存率，减轻体温下降和体重减轻，降低支气管肺泡灌洗液（BALF）中的蛋白和炎性细胞因子水平，并加速体内细菌清除[7]。BOS-318（10mg/kg）在电生理实验前24小时单次口服给予成年C57BL/6小。BOS-318能够显著抑制组织中的弗林蛋白酶活性，并阻止PAR1激动剂TFLLR-NH2对神经肌肉传递的增强作用[8]。