Salvador Guilherme H M, Pinto Êmylle K R, Ortolani Paula L, Fortes-Dias Consuelo L, Cavalcante Walter L G, Soares Andreimar M, Lomonte Bruno, Lewin Matthew R, Fontes Marcos R M
Departamento de Biofísica e Farmacologia, Instituto de Biociências, Universidade Estadual Paulista, Botucatu, SP, Brazil.
Departmento de Farmacologia, Instituto de Ciências Biologicas, Universidade Federal de Minas Gerais (UFMG), Brazil.
Biochimie. 2023 Apr;207:1-10. doi: 10.1016/j.biochi.2022.11.006. Epub 2022 Nov 17.
Varespladib (LY315920) is a potent inhibitor of human group IIA phospholipase A (PLA) originally developed to control inflammatory cascades of diseases associated with high or dysregulated levels of endogenous PLA. Recently, varespladib was also found to inhibit snake venom PLA and PLA-like toxins. Herein, ex vivo neuromuscular blocking activity assays were used to test the inhibitory activity of varespladib. The binding affinity between varespladib and a PLA-like toxin was quantified and compared with other potential inhibitors for this class of proteins. Crystallographic and bioinformatic studies showed that varespladib binds to PrTX-I and BthTX-I into their hydrophobic channels, similarly to other previously characterized PLA-like myotoxins. However, a new finding is that an additional varespladib binds to the MDiS region, a particular site that is related to muscle cell disruption by these toxins. The present results further advance the characterization of the molecular interactions of varespladib with PLA-like myotoxins and provide additional evidence for this compound as a promising inhibitor candidate for different PLA and PLA-like toxins.
伐瑞普拉迪布（LY315920）是一种强效的人IIA组磷脂酶A（PLA）抑制剂，最初研发用于控制与内源性PLA水平升高或失调相关疾病的炎症级联反应。最近，还发现伐瑞普拉迪布可抑制蛇毒PLA和PLA样毒素。在此，采用体外神经肌肉阻滞活性测定法来测试伐瑞普拉迪布的抑制活性。对伐瑞普拉迪布与一种PLA样毒素之间的结合亲和力进行了定量分析，并与这类蛋白质的其他潜在抑制剂进行了比较。晶体学和生物信息学研究表明，与其他先前已表征的PLA样肌毒素类似，伐瑞普拉迪布通过其疏水通道与PrTX-I和BthTX-I结合。然而，一项新发现是，另有一个伐瑞普拉迪布分子与MDiS区域结合，该区域是这些毒素导致肌肉细胞破坏的一个特定部位。目前的结果进一步推进了对伐瑞普拉迪布与PLA样肌毒素分子相互作用的表征，并为该化合物作为不同PLA和PLA样毒素的一种有前景的抑制剂候选物提供了更多证据。
