Bacteriology Laboratory, Butantan Institute, São Paulo 05585-000, Brazil.
Institute of Biomedical Research, National Autonomous University of Mexico, Mexico City 04510, Mexico.
Int J Mol Sci. 2024 Sep 30;25(19):10555. doi: 10.3390/ijms251910555.
Several natural products are being studied to identify new bioactive molecules with therapeutic potential for infections, immune modulation, and other pathologies. TLRs are a family of receptors that play a crucial role in the immune system, constituting the first line of immune defense. They recognize specific products derived from microorganisms that activate multiple pathways and transcription factors in target cells, which are vital for producing immune mediators. Mygalin is a synthetic acylpolyamine derived from hemocytes of the spider . This molecule negatively regulates macrophage response to LPS stimulation by interacting with MD2 in the TLR4/MD2 complex. Here, we investigated the activity of Mygalin mediated by TLR2 agonists in cells treated with Pam3CSK4 (TLR2/1), Pam2CSK4, Zymosan (TLR2/6), and IFN-γ. Our data showed that Mygalin significantly inhibited stimulation with agonists and IFN-γ, reducing NO and IL-6 synthesis, regardless of the stimulation. There was also a significant reduction in the phosphorylation of proteins NF-κB p65 and STAT-1 in cells treated with Pam3CSK4. Molecular docking assays determined the molecular structure of Mygalin and agonists Pam3CSK4, Pam2CSK4, and Zymosan, as well as their interaction and free energy with the heterodimeric complexes TLR2/1 and TLR2/6. Mygalin interacted with the TLR1 and TLR2 dimer pathway through direct interaction with the agonists, and the ligand-binding domain was similar in both complexes. However, the binding of Mygalin was different from that of the agonists, since the interaction energy with the receptors was lower than with the agonists for their receptors. In conclusion, this study showed the great potential of Mygalin as a potent natural inhibitor of TLR2/1 and TLR2/6 and a suppressor of the inflammatory response induced by TLR2 agonists, in part due to its ability to interact with the heterodimeric complexes.
几种天然产物正在被研究，以鉴定具有治疗感染、免疫调节和其他病理学潜力的新生物活性分子。TLRs 是一类受体，在免疫系统中发挥关键作用，构成免疫防御的第一道防线。它们识别来自微生物的特定产物，这些产物激活靶细胞中的多种途径和转录因子，对于产生免疫介质至关重要。Mygalin 是一种源自蜘蛛血细胞的合成酰多胺。该分子通过与 TLR4/MD2 复合物中的 MD2 相互作用，负调控巨噬细胞对 LPS 刺激的反应。在这里，我们研究了 TLR2 激动剂介导的 Mygalin 在经 Pam3CSK4（TLR2/1）、Pam2CSK4、Zymosan（TLR2/6）和 IFN-γ处理的细胞中的活性。我们的数据表明，Mygalin 显著抑制激动剂和 IFN-γ的刺激，减少 NO 和 IL-6 的合成，而与刺激无关。用 Pam3CSK4 处理的细胞中 NF-κB p65 和 STAT-1 蛋白的磷酸化也显著降低。分子对接试验确定了 Mygalin 和激动剂 Pam3CSK4、Pam2CSK4 和 Zymosan 的分子结构，以及它们与 TLR2/1 和 TLR2/6 异二聚体复合物的相互作用和自由能。Mygalin 通过与激动剂的直接相互作用与 TLR1 和 TLR2 二聚体途径相互作用，并且两个复合物中的配体结合域相似。然而，Mygalin 的结合与激动剂不同，因为与受体的相互作用能低于与受体的激动剂。总之，这项研究表明 Mygalin 作为 TLR2/1 和 TLR2/6 的有效天然抑制剂和 TLR2 激动剂诱导的炎症反应的抑制剂具有巨大的潜力，部分原因是其与异二聚体复合物相互作用的能力。
