There is a strong need for a new broad-spectrum antiinfluenza therapeutic, as vaccination and existing treatments are only moderately effective. We previously engineered a lectin, H84T banana lectin (H84T), to retain broad-spectrum activity against multiple influenza strains, including pandemic and avian, while largely eliminating the potentially harmful mitogenicity of the parent compound. The amino acid mutation at position 84 from histidine to threonine minimizes the mitogenicity of the wild-type lectin while maintaining antiinfluenza activity in vitro. We now report that in a lethal mouse model H84T is indeed nonmitogenic, and both early and delayed therapeutic administration of H84T intraperitoneally are highly protective, as is H84T administered subcutaneously. Mechanistically, attachment, which we anticipated to be inhibited by H84T, was only somewhat decreased by the lectin. Instead, H84T is internalized into the late endosomal/lysosomal compartment and inhibits virus-endosome fusion. These studies reveal that H84T is efficacious against influenza virus in vivo, and that the loss of mitogenicity seen previously in tissue culture is also seen in vivo, underscoring the potential utility of H84T as a broad-spectrum antiinfluenza agent.

中文翻译：

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分子工程抗病毒香蕉凝集素可抑制融合，可有效抵抗体内流感病毒感染。

由于疫苗接种和现有治疗方法效果有限，因此迫切需要一种新的广谱抗流感治疗方法。我们之前设计了一种凝集素，即 H84T 香蕉凝集素 (H84T)，以保留针对多种流感病毒株（包括大流行性流感病毒株和禽流感病毒株）的广谱活性，同时在很大程度上消除母体化合物潜在有害的有丝分裂性。第 84 位的氨基酸从组氨酸突变为苏氨酸，最大限度地降低了野生型凝集素的有丝分裂活性，同时保持了体外抗流感活性。我们现在报道，在致死小鼠模型中，H84T 确实是非促有丝分裂的，并且腹膜内早期和延迟治疗性施用 H84T 都具有高度保护性，就像皮下施用 H84T 一样。从机制上讲，我们预计 H84T 会抑制附着，但凝集素仅在一定程度上减少了附着。相反，H84T 内化到晚期内体/溶酶体区室中并抑制病毒-内体融合。这些研究表明，H84T 在体内对流感病毒有效，并且之前在组织培养中观察到的有丝分裂能力的丧失在体内也出现，强调了 H84T 作为广谱抗流感药物的潜在用途。