Parasitic diseases cause significant global morbidity and mortality particularly in the poorest regions of the world. Schistosomiasis, one of the most widespread neglected tropical diseases, affects more than 200 million people worldwide. Histone deacetylase (HDAC) inhibitors are prominent epigenetic drugs that are being investigated in the treatment of several diseases, including cancers and parasitic diseases. Schistosoma mansoni HDAC8 (SmHDAC8) is highly expressed in all life cycle stages of the parasite, and selective inhibition is required in order to avoid undesirable off-target effects in the host. Herein, by X-ray crystal structures of SmHDAC8-inhibitor complexes, biochemical and phenotypic studies, we found two schistosomicidal spiroindoline derivatives binding a novel site, next to Trp198, on the enzyme surface. We determined that by acting on this site, either by mutation of the Trp198 or by compound binding, a decrease in the activity of the enzyme is achieved. Remarkably, this allosteric site differs from the human counterpart; rather, it is conserved in all Schistosoma species, as well as Rhabidoptera and Trematoda classes, thus paving the way for the design of HDAC8-selective allosteric inhibitors with improved properties.

寄生虫病导致严重的全球发病率和死亡率，特别是在世界上最贫穷的地区。血吸虫病是最普遍被忽视的热带疾病之一，影响着全世界 2 亿多人。组蛋白脱乙酰酶 (HDAC) 抑制剂是重要的表观遗传药物，正在研究用于治疗多种疾病，包括癌症和寄生虫病。曼氏血吸虫HDAC8 ( Sm HDAC8) 在寄生虫的所有生命周期阶段都高度表达，需要选择性抑制以避免在宿主中产生不良的脱靶效应。在此，通过Sm的 X 射线晶体结构HDAC8 抑制剂复合物、生化和表型研究，我们发现两种杀血吸虫性螺吲哚啉衍生物结合酶表面上 Trp198 旁边的一个新位点。我们确定通过作用于该位点，通过突变 Trp198 或通过化合物结合，可以降低酶的活性。值得注意的是，这个变构位点与人类对应的变构位点不同。相反，它在所有血吸虫物种以及横纹翅目和吸虫纲中都是保守的，从而为设计具有改进特性的 HDAC8 选择性变构抑制剂铺平了道路。