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Mpox virus (formerly monkeypox virus [MPXV]) is a neglected zoonotic pathogen that caused a worldwide outbreak in May 2022. Given the lack of an established therapy, the development of an anti-MPXV strategy is of vital importance. To identify drug targets for the development of anti-MPXV agents, we screened a chemical library using an MPXV infection cell assay and found that gemcitabine, trifluridine, and mycophenolic acid (MPA) inhibited MPXV propagation. These compounds showed broad-spectrum anti-orthopoxvirus activities and presented lower 90% inhibitory concentrations (0.026 to 0.89 μM) than brincidofovir, an approved anti-smallpox agent. These three compounds have been suggested to target the postentry step to reduce the intracellular production of virions. Knockdown of IMP dehydrogenase (IMPDH), the rate-limiting enzyme of guanosine biosynthesis and a target of MPA, dramatically reduced MPXV DNA production. Moreover, supplementation with guanosine recovered the anti-MPXV effect of MPA, suggesting that IMPDH and its guanosine biosynthetic pathway regulate MPXV replication. By targeting IMPDH, we identified a series of compounds with stronger anti-MPXV activity than MPA. This evidence shows that IMPDH is a potential target for the development of anti-MPXV agents. Mpox is a zoonotic disease caused by infection with the mpox virus, and a worldwide outbreak occurred in May 2022. The smallpox vaccine has recently been approved for clinical use against mpox in the United States. Although brincidofovir and tecovirimat are drugs approved for the treatment of smallpox by the U.S. Food and Drug Administration, their efficacy against mpox has not been established. Moreover, these drugs may present negative side effects. Therefore, new anti-mpox virus agents are needed. This study revealed that gemcitabine, trifluridine, and mycophenolic acid inhibited mpox virus propagation and exhibited broad-spectrum anti-orthopoxvirus activities. We also suggested IMP dehydrogenase as a potential target for the development of anti-mpox virus agents. By targeting this molecule, we identified a series of compounds with stronger anti-mpox virus activity than mycophenolic acid.

猴痘病毒（以前称为猴痘病毒 [MPXV]）是一种被忽视的人畜共患病原体，它于 2022 年 5 月在全球范围内引发了一次暴发。鉴于缺乏既定的治疗方法，开发抗 MPXV 策略至关重要。为了确定开发抗 MPXV 药物的靶点，我们使用 MPXV 感染细胞测定法筛选了一个化学文库，发现吉西他滨、三氟尿苷和霉酚酸（MPA）抑制了 MPXV 的繁殖。这些化合物显示出广谱抗正痘病毒活性，并且其 90%抑制浓度（0.026 至 0.89 μM）低于已批准的抗天花药物溴夫定。这三种化合物已被建议针对进入后步骤，以减少病毒粒子的细胞内产生。IMP 脱氢酶（IMPDH）的敲低，即鸟嘌呤生物合成的限速酶和 MPA 的靶标，显著降低了 MPXV DNA 的产生。此外，补充鸟嘌呤恢复了 MPA 的抗 MPXV 作用，表明 IMPDH 及其鸟嘌呤生物合成途径调节 MPXV 复制。通过靶向 IMPDH，我们鉴定了一系列比 MPA 具有更强抗 MPXV 活性的化合物。这一证据表明，IMPDH 是开发抗 MPXV 药物的潜在靶标。

猴痘是一种由感染猴痘病毒引起的人畜共患病，2022 年 5 月在全球范围内暴发。在美国，最近已批准天花疫苗用于临床治疗猴痘。尽管溴夫定和特考韦瑞已被美国食品和药物管理局批准用于治疗天花，但它们对猴痘的疗效尚未确定。此外，这些药物可能存在负面副作用。因此，需要新的抗猴痘病毒药物。本研究表明，吉西他滨、三氟尿苷和霉酚酸抑制猴痘病毒的繁殖，并表现出广谱抗正痘病毒活性。我们还提出 IMP 脱氢酶作为开发抗猴痘病毒药物的潜在靶标。通过靶向该分子，我们鉴定了一系列比霉酚酸具有更强抗猴痘病毒活性的化合物。