药物查揭示了针对Mpox病毒的新型强效宿主向抗病毒药物
bioRxiv : the preprint server for biology
|May 22, 2025
概括
新的宿主定向激酶抑制剂对Mpox病毒 (MPXV) 有希望. 这项研究确定了有效的化合物,可以减少MPXV复制和皮肤病变,为这种重新出现的动物性疾病威胁提供新的治疗途径.
科学领域:
- 病毒学 病毒学
- 药物发现 药物发现 药物发现
- 传染性疾病 传染性疾病
背景情况:
- 马普克斯病毒 (MPXV) 构成了重新出现的动物性疾病威胁,最近的全球疫情是由增加的传染性驱动的.
- 现有的治疗方法,如tecovirimat (TPOXX) 的有效性有限,需要开发新的抗病毒疗法.
- 世界卫生组织已将Mpox疫情宣布为公共卫生紧急情况.
研究的目的:
- 通过高通量查来识别针对MPXV的新型抗病毒化合物.
- 评估已识别的化合物的有效性,以减少MPXV复制和相关的细胞病变效应.
- 探索MPXV感染的新治疗策略.
主要方法:
- 针对MPXV (Clade IIb) 进行了2,750个化合物主导激酶抑制剂库的高通量选.
- 进行初级,二级和三级查,以确定强效和无毒的抗病毒化合物.
- 用初级人类表皮皮质角质细胞和MPXV皮肤感染的体内小鼠模型进行了体外测试以验证.
主要成果:
- 确定了138种抑制MPXV细胞病变效应的化合物,包括EGFR,PI3K-mTOR,Ras/Raf的抑制剂,以及亡和自的调节剂.
- 入围名单中的强效,无毒的化合物可以抑制MPXV复制.
- 三种化合物 (IRAK4-IN-6,SM-7368,KRAS抑制剂-10) 减少了MPXV诱导的细胞死亡,调节了NF-κB和STING信号传递,并减少了小鼠的皮肤病变和病毒负担.
结论:
- 揭示了针对MPXV.有效的新类宿主导抗病毒化合物.
- 伊拉克4-IN-6和SM-7368显示出MPXV治疗的巨大潜力.
- 确定了针对MPXV的未来临床开发的有希望的候选者.
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