Actinonin

Actinonin, a peptidomimetic antibiotic that inhibits enkephalin-aminopeptidase, enkephalinase A, and dipeptidylaminopeptidase with IC₅₀ values of 0.39μM, 5.6μM, and 1.1μM, respectively^[1]. Actinonin can inhibit the constitutive expression of functional recombinant MT1-MMP protein, block the activation of proMMP-2, and suppress angiogenesis^[2]. Actinonin has been widely used as an antibacterial agent to inhibit the growth of Gram-positive bacteria and difficult-to-culture Gram-negative bacteria^[3].

In vitro, Actinonin treatment for 5 days significantly inhibited the viability of HL-60 cells, NB4 cells and AKR cells with IC₅₀ values of 2µg/ml, 5µg/ml, and 3µg/ml, respectively^[4]. Treatment of U937 cells with 20μg/ml of Actinonin for 24 hours significantly induced cell apoptosis, accompanied by a significant increase in the activities of caspase-3 and caspase-7-like enzymes and extensive fragmentation of DNA^[5]. Actinonin pretreatment at 26nM for 1 hour can reduce the expression of HSP70 induced by celastrol in U937 cells, and synergistically inhibit cell proliferation with celastrol^[6].

In vivo, Actinonin treatment via daily intraperitoneal injection (150mg/kg/day) for 2 weeks significantly inhibited tumor growth in the A549 xenograft mouse model without causing any toxic reactions^[7]. Thirty minutes before the mice underwent cecal ligation and puncture (CLP), a single dose of Actinonin (20mg/kg) was injected intraperitoneally, which could reduce the serum IL-1β level and prevent the decline in renal capillary perfusion^[8].

References:
[1] Hachisu M, Hiranuma T, Murata S, et al. Analgesic effect of actinonin, a new potent inhibitor of multiple enkephalin degrading enzymes[J]. Life sciences, 1987, 41(2): 235-240.
[2] Sina A, Lord-Dufour S, Annabi B. Cell-based evidence for aminopeptidase N/CD13 inhibitor actinonin targeting of MT1-MMP-mediated proMMP-2 activation[J]. Cancer letters, 2009, 279(2): 171-176.
[3] Chen D Z, Patel D V, Hackbarth C J, et al. Actinonin, a naturally occurring antibacterial agent, is a potent deformylase inhibitor[J]. Biochemistry, 2000, 39(6): 1256-1262.
[4] Xu Y, Lai L T, Gabrilove J L, et al. Antitumor activity of actinonin in vitro and in vivo[J]. Clinical cancer research: an official journal of the American Association for Cancer Research, 1998, 4(1): 171-176.
[5] Grujic M, Zavasnik-Bergant T, Pejler G, et al. Actinonin induces apoptosis in U937 leukemia cells[J]. Cancer letters, 2005, 223(2): 211-218.
[6] Peng B, Zhang X, Cao F, et al. Peptide deformylase inhibitor actinonin reduces celastrol’s HSP70 induction while synergizing proliferation inhibition in tumor cells[J]. Bmc Cancer, 2014, 14(1): 146.
[7] Lee M D, She Y, Soskis M J, et al. Human mitochondrial peptide deformylase, a new anticancer target of actinonin-based antibiotics[J]. The Journal of clinical investigation, 2004, 114(8): 1107-1116.
[8] Wang Z, Herzog C, Kaushal G P, et al. Actinonin, a meprin A inhibitor, protects the renal microcirculation during sepsis[J]. Shock, 2011, 35(2): 141-147.

Actinonin是一种肽模拟抗生素，能够抑制enkephalin-aminopeptidase、enkephalinase A和 dipeptidylaminopeptidase，IC₅₀值分别为0.39μM、5.6μM和1.1μM^[1]。Actinonin能抑制功能性重组MT1-MMP蛋白的组成型表达，阻断proMMP-2的活化，并抑制血管生成^[2]。Actinonin已被广泛用作抗菌剂，以抑制革兰氏阳性菌和难培养的革兰氏阴性菌的生长^[3]。

在体外，Actinonin处理5天能显著抑制HL-60细胞、NB4细胞和AKR细胞的活力，IC₅₀值分别为2µg/ml、5µg/ml和3µg/ml^[4]。用20μg/ml的Actinonin处理U937细胞24小时，能显著诱导细胞凋亡，同时caspase-3和caspase-7样酶的活性显著增加，并出现广泛的DNA片段化^[5]。用26nM的Actinonin预处理U937细胞1小时，可降低celastrol诱导的HSP70表达，并与celastrol协同抑制细胞增殖^[6]。

在体内，通过每日腹腔注射Actinonin（150mg/kg/day）治疗2周，能显著抑制A549异种移植小鼠模型的肿瘤生长，且不引起任何毒性反应^[7]。在小鼠接受盲肠结扎穿孔术（CLP）前30分钟，单次腹腔注射Actinonin（20mg/kg），可降低血清IL-1β水平并防止肾毛细血管灌注下降^[8]。