N-Boc-Phe-Leu-Phe-Leu-Phe is an antagonist of formyl peptide receptor (FPR) 1, with the apparent dissociation constant KD of 230nM[1]. N-Boc-Phe-Leu-Phe-Leu-Phe inhibits neutrophil chemotaxis induced by FPR1, and suppresses the production of superoxide[2]. N-Boc-Phe-Leu-Phe-Leu-Phe has been widely used as a model compound to develop a series of derivatives and is employed as a positron emission tomography imaging agent[1,3].
In vitro, N-Boc-Phe-Leu-Phe-Leu-Phe treatment at 120μM for 48h inhibited VEGF-A165-mediated human umbilical vein endothelial cell (HUVEC) proliferation and blocked the activation of the downstream secondary signaling mediators EKR1/2 and AKT[4]. Treatment of rat conjunctival goblet cells with N-Boc-Phe-Leu-Phe-Leu-Phe (0.1mM) for 30 minutes would affect the intracellular calcium ion concentration regulated by Maresin 2 and reduce the response of lipoxin (LX) A4[5].
In, vivo, N-Boc-Phe-Leu-Phe-Leu-Phe treatment via intraperitoneal injections (1mg/kg) twice a week for 8 weeks significantly inhibited the anti-fibrotic effect of Ac2-26 in mice with liver fibrosis and promoted liver inflammation induced by CCl4[6]. Intraperitoneal injection of N-Boc-Phe-Leu-Phe-Leu-Phe (1μl; 10mM) every other day for 6 consecutive days can block the renal injury repair effect of BML-111 in the diabetic mouse model[7].
References:
[1] Hayashi R, Kitajima T, Mizuguchi H, et al. Development of potent antagonists for formyl peptide receptor 1 based on Boc-Phe-D-Leu-Phe-D-Leu-Phe-OH[J]. Bioorganic & Medicinal Chemistry, 2014, 22(15): 3824-3828.
[2] Stenfeldt A L, Karlsson J, Wennerås C, et al. Cyclosporin H, Boc-MLF and Boc-FLFLF are antagonists that preferentially inhibit activity triggered through the formyl peptide receptor[J]. Inflammation, 2007, 30(6): 224-229.
[3] Dalpiaz A, Ferretti M E, Vertuani G, et al. C-and N-terminal residue effect on peptide derivatives' antagonism toward the formyl-peptide receptor[J]. European journal of pharmacology, 2002, 436(3): 187-196.
[4] Nawaz I M, Chiodelli P, Rezzola S, et al. N-tert-butyloxycarbonyl-Phe-Leu-Phe-Leu-Phe (BOC2) inhibits the angiogenic activity of heparin-binding growth factors[J]. Angiogenesis, 2018, 21(1): 47-59.
[5] Olsen M V, Lyngstadaas A V, Bair J A, et al. Signaling pathways used by the specialized pro-resolving mediator maresin 2 regulate goblet cell function: Comparison with maresin 1[J]. International journal of molecular sciences, 2022, 23(11): 6233.
[6] Fan J H, Luo N, Liu G F, et al. Mechanism of annexin A1/N-formylpeptide receptor regulation of macrophage function to inhibit hepatic stellate cell activation through Wnt/β-catenin pathway[J]. World Journal of Gastroenterology, 2023, 29(22): 3422.
[7] Hao H, Xie F, Xu F, et al. LipoxinA4 analog BML-111 protects podocytes cultured in high-glucose medium against oxidative injury via activating Nrf2 pathway[J]. International Immunopharmacology, 2022, 111: 109170.
N-Boc-Phe-Leu-Phe-Leu-Phe是一种甲酰肽受体（FPR）1拮抗剂，表观解离常数KD为230nM[1]。N-Boc-Phe-Leu-Phe-Leu-Phe可抑制FPR1诱导的中性粒细胞趋化作用，并抑制超氧化物的产生[2]。N-Boc-Phe-Leu-Phe-Leu-Phe模型先导化合物被广泛用于开发一系列衍生物，并作为正电子发射断层扫描成像剂使用[1,3]。
在体外，120μM的N-Boc-Phe-Leu-Phe-Leu-Phe处理48小时可抑制VEGF-A165介导的人脐静脉内皮细胞(HUVEC)增殖，并阻断下游信号介质ERK1/2和AKT的激活[4]。0.1mM的N-Boc-Phe-Leu-Phe-Leu-Phe处理大鼠结膜杯状细胞30分钟会影响Maresin 2调控的细胞内钙离子浓度，并降低脂毒素（LX）A4的响应[5]。
在体内，肝纤维化小鼠每周两次腹腔注射N-Boc-Phe-Leu-Phe-Leu-Phe（1mg/kg；持续8周）可显著抑制Ac2-26的抗纤维化作用，并促进CCl4诱导的肝脏炎症[6]。糖尿病小鼠模型隔日腹腔注射N-Boc-Phe-Leu-Phe-Leu-Phe（1μl; 10mM；持续6天）能阻断BML-111的肾损伤修复作用[7]。