Department of General Pathology and Pathological Physiology, Institute of Experimental Medicine, Academician Pavlov Street 12, 197376 Saint Petersburg, Russia.
M.M. Shemyakin and Yu. A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Street, 16/10, 117997 Moscow, Russia.
Mar Drugs. 2022 Sep 28;20(10):612. doi: 10.3390/md20100612.
The widespread resistance to antibiotics in pathogenic bacteria makes the development of a new generation of antimicrobials an urgent task. The development of new antibiotics must be accompanied by a comprehensive study of all of their biological activities in order to avoid adverse side-effects from their application. Some promising antibiotic prototypes derived from the structures of arenicins, antimicrobial peptides from the lugworm , have been developed. Previously, we described the ability of natural arenicins -1 and -2 to modulate the human complement system activation in vitro. In this regard, it seems important to evaluate the effect of therapeutically promising arenicin analogues on complement activation. Here, we describe the complement-modulating activity of three such analogues, Ar-1[V8R], ALP1, and AA139. We found that the mode of action of Ar-1[V8R] and ALP1 on the complement was similar to that of natural arenicins, which can both activate and inhibit the complement, depending on the concentration. However, Ar-1[V8R] behaved predominantly as an inhibitor, showing only a moderate increase in C3a production in the alternative pathway model and no enhancement at all of the classical pathway of complement activation. In contrast, the action of ALP1 was characterized by a marked increase in the complement activation through the classical pathway in the concentration range of 2.5-20 μg/mL. At the same time, at higher concentrations (80-160 μg/mL), this peptide exhibited a complement inhibitory effect characteristic of the other arenicins. Peptide AA139, like other arenicins, exhibited an inhibitory effect on complement at a concentration of 160 μg/mL, but was much less pronounced. Overall, our results suggest that the effect on the complement system should be taken into account in the development of antibiotics based on arenicins.
在致病细菌中广泛存在的抗生素耐药性使得开发新一代抗菌药物成为一项紧迫的任务。开发新的抗生素必须全面研究其所有的生物学活性，以避免其应用带来的不良反应。从沙蚕抗菌肽中衍生出的一些有前途的抗生素原型，如arenicins，已经被开发出来。此前，我们描述了天然arenicins-1 和 -2 调节体外人补体系统激活的能力。在这方面，评估有治疗前景的arenicin 类似物对补体激活的影响似乎很重要。在这里，我们描述了三种类似物，Ar-1[V8R]、ALP1 和 AA139 的补体调节活性。我们发现，Ar-1[V8R]和 ALP1 对补体的作用模式与天然 arenicins 相似，它们可以根据浓度激活和抑制补体。然而，Ar-1[V8R]主要表现为抑制剂，在替代途径模型中仅适度增加 C3a 产生，而在经典途径中根本没有增强补体激活。相比之下，ALP1 的作用特点是在 2.5-20 μg/mL 的浓度范围内通过经典途径明显增加补体激活。同时，在更高的浓度（80-160 μg/mL）下，这种肽表现出与其他 arenicins 相似的补体抑制作用。肽 AA139 与其他 arenicins 一样，在 160 μg/mL 的浓度下对补体表现出抑制作用，但效果要差得多。总的来说，我们的结果表明，在基于 arenicins 的抗生素开发中，应该考虑对补体系统的影响。
