Porcine reproductive and respiratory syndrome (PRRS) is one of the most economically devastating diseases affecting the pork industry globally. PRRS is caused by PRRS virus (PRRSV). Currently there are no effective treatments against this swine disease. Through artificial intelligence molecular screening, we obtained a set of small molecule compounds predicted to target the scavenger receptor cysteine-rich domain 5 (SRCR5) of CD163, which is a cell surface receptor specific for PRRSV infection. These compounds were screened using a cell-based bimolecular fluorescence complementation (BiFC) assay, and the function of positive hit was further evaluated and validated by PRRSV-infection assay using porcine alveolar macrophages (PAMs). Using the BiFC assay, we identified one compound with previously unverified function, 4-Fluoro-2-methyl-N-[3-(3-morpholin-4-ylsulfonylanilino)quinoxalin-2-yl]benzenesulfonamide (designated here as B7), that significantly inhibits the interaction between the PRRSV glycoprotein (GP2a or GP4) and the CD163-SRCR5 domain. We further demonstrated that compound B7 inhibits PRRSV infection of PAMs, the primary target of PRRSV in a dose-dependent manner. B7 significantly inhibited the infection caused by both type I and type II PRRSV strains. Further comparison and functional evaluation of chemical compounds structurally related to B7 revealed that the 3-(morpholinosulfonyl)aniline moiety of B7 or the 3-(piperidinylsulfonyl)aniline moiety in a B7 analogue is important for the inhibitory function against PRRSV infection. Our study identified a novel strategy to potentially prevent PRRSV infection in pigs by blocking the PRRSV-CD163 interaction with small molecules.

中文翻译：

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小分子阻碍了猪繁殖与呼吸综合征病毒和CD163受体与猪细胞感染之间的相互作用。

猪繁殖与呼吸综合症（PRRS）是影响全球猪肉行业的最具经济破坏力的疾病之一。PRRS是由PRRS病毒（PRRSV）引起的。当前没有针对这种猪疾病的有效疗法。通过人工智能分子筛选，我们获得了一组预期靶向CD163的清除剂受体富含半胱氨酸的结构域5（SRCR5）的小分子化合物，CD163是PRRSV感染的特异细胞表面受体。使用基于细胞的双分子荧光互补（BiFC）分析法筛选这些化合物，并使用猪肺泡巨噬细胞（PAM）通过PRRSV感染分析法进一步评估和验证阳性命中的功能。使用BiFC分析，我们确定了一种以前未经验证的化合物，4-氟-2-甲基-N- [3-（3-吗啉-4-基磺酰羊毛脂基）喹喔啉-2-基]苯磺酰胺（在此指定为B7），可显着抑制PRRSV糖蛋白（GP2a或GP4）之间的相互作用和CD163-SRCR5域。我们进一步证明了化合物B7以剂量依赖的方式抑制PRAM的PRRSV感染。B7显着抑制了由I型和II型PRRSV毒株引起的感染。对与B7结构相关的化合物的进一步比较和功能评估表明，B7的B7的3-（吗啉代磺酰基）苯胺部分或B7类似物的3-（哌啶基磺酰基）苯胺部分对于抵抗PRRSV感染具有重要的作用。