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Receptor-Based Peptides for Inhibition of Leukotoxin Activity
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2018-05-09 00:00:00 , DOI: 10.1021/acsinfecdis.7b00230
Eric Krueger 1 , Shannon Hayes 1 , En Hyung Chang 1 , Shailagne Yutuc 1 , Angela C. Brown 1
Affiliation  

The Gram-negative bacterium Aggregatibacter actinomycetemcomitans, commonly associated with localized aggressive periodontitis (LAP), secretes an RTX (repeats-in-toxin) protein leukotoxin (LtxA) that targets human white blood cells, an interaction that is driven by its recognition of the lymphocyte function-associated antigen-1 (LFA-1) integrin. In this study, we report on the inhibition of LtxA-LFA-1 binding as an antivirulence strategy to inhibit LtxA-mediated cytotoxicity. Specifically, we designed and synthesized peptides corresponding to the reported LtxA binding domain on LFA-1 and characterized their capability to inhibit LtxA binding to LFA-1 and subsequent cytotoxic activity in human immune cells. We found that several of these peptides, corresponding to sequential β-strands in the LtxA-binding domain of LFA-1, inhibit LtxA activity, demonstrating the effectiveness of this approach. Further investigations into the mechanism by which these peptides inhibit LtxA binding to LFA-1 reveal a correlation between toxin-peptide affinity and LtxA-mediated cytotoxicity, leading to a diminished association between LtxA and LFA-1 on the cell membrane. Our results demonstrate the possibility of using target-based peptides to inhibit LtxA activity, and we expect that a similar approach could be used to hinder the activity of other RTX toxins.

中文翻译:

抑制白细胞毒素活性的基于受体的肽

革兰氏阴性菌放线菌通常与局部侵袭性牙周炎(LAP)相关,它会分泌靶向人白细胞的RTX(毒素重复序列)蛋白白细胞毒素(LtxA),这种相互作用是由其对淋巴细胞功能相关抗原1的识别驱动的(LFA-1)整联蛋白。在这项研究中,我们报告了抑制LtxA-LFA-1结合作为一种抑制LtxA介导的细胞毒性的抗毒策略。具体而言,我们设计和合成了与LFA-1上已报道的LtxA结合结构域相对应的肽,并表征了其抑制LtxA与LFA-1结合的能力以及随后在人免疫细胞中的细胞毒活性。我们发现这些肽中的几种,对应于LFA-1的LtxA结合域中的顺序β链,抑制LtxA活性,证明了这种方法的有效性。这些肽抑制LtxA与LFA-1结合的机制的进一步研究揭示了毒素-肽亲和力与LtxA介导的细胞毒性之间的相关性,导致LtxA与LFA-1在细胞膜上的缔合减少。我们的结果证明了使用基于靶标的肽抑制LtxA活性的可能性,并且我们希望可以使用类似的方法来阻止其他RTX毒素的活性。
更新日期:2018-05-09
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