North John R, Takenaka Shunsuke, Rozek Annett, Kielczewska Agnieszka, Opal Steven, Morici Lisa A, Finlay B Brett, Schaber Christopher J, Straube Richard, Donini Oreola
Inimex Pharmaceuticals Inc., 8540 Baxter Place, Burnaby, BC V5A 4T8, Canada.
The Warren Alpert Medical School of Brown University, Pawtucket, RI 02912, United States.
J Biotechnol. 2016 May 20;226:24-34. doi: 10.1016/j.jbiotec.2016.03.032. Epub 2016 Mar 23.
Innate Defense Regulators (IDRs) are short synthetic peptides that target the host innate immune system via an intracellular adaptor protein which functions at key signaling nodes. In this work, further details of the mechanism of action of IDRs have been discovered. The studies reported here show that the lead clinical IDR, SGX94, has broad-spectrum activity against Gram-negative and Gram-positive bacterial infections caused by intracellular or extracellular bacteria and also complements the actions of standard of care antibiotics. Based on in vivo and primary cell culture studies, this activity is shown to result from the primary action of SGX94 on tissue-resident cells and subsequent secondary signaling to activate myeloid-derived cells, resulting in enhanced bacterial clearance and increased survival. Data from non-clinical and clinical studies also show that SGX94 treatment modulates pro-inflammatory and anti-inflammatory cytokine levels, thereby mitigating the deleterious inflammatory consequences of innate immune activation. Since they act through host pathways to provide both broad-spectrum anti-infective capability as well as control of inflammation, IDRs are unlikely to be impacted by resistance mechanisms and offer potential clinical advantages in the fight against emerging and antibiotic resistant bacterial infections.
固有防御调节剂（IDRs）是短的合成肽，它们通过在关键信号节点起作用的细胞内衔接蛋白靶向宿主固有免疫系统。在这项工作中，已发现IDRs作用机制的更多细节。此处报道的研究表明，主要的临床IDR——SGX94，对由细胞内或细胞外细菌引起的革兰氏阴性和革兰氏阳性细菌感染具有广谱活性，并且还能补充标准护理抗生素的作用。基于体内和原代细胞培养研究，这种活性被证明是由SGX94对组织驻留细胞的主要作用以及随后激活髓系来源细胞的次级信号传导所导致的，从而增强细菌清除并提高存活率。非临床和临床研究的数据还表明，SGX94治疗可调节促炎和抗炎细胞因子水平，从而减轻固有免疫激活的有害炎症后果。由于它们通过宿主途径发挥作用，既能提供广谱抗感染能力又能控制炎症，因此IDRs不太可能受到耐药机制的影响，并且在对抗新出现的和抗生素耐药的细菌感染方面具有潜在的临床优势。
