PDF(Pubmed)
Abstract：
Monkeypox virus (MPXV) infections in humans have historically been restricted to regions of endemicity in Africa. However, in 2022, an alarming number of MPXV cases were reported globally, with evidence of person-to-person transmission. Because of this, the World Health Organization (WHO) declared the MPXV outbreak a public health emergency of international concern. The supply of MPXV vaccines is limited, and only two antivirals, tecovirimat and brincidofovir, approved by the U.S. Food and Drug Administration (FDA) for the treatment of smallpox, are currently available for the treatment of MPXV infection. Here, we evaluated 19 compounds previously shown to inhibit different RNA viruses for their ability to inhibit orthopoxvirus infections. We first used recombinant vaccinia virus (rVACV) expressing fluorescence (mScarlet or green fluorescent protein [GFP]) and luciferase (Nluc) reporter genes to identify compounds with antiorthopoxvirus activity. Seven compounds from the ReFRAME library (antimycin A, mycophenolic acid, AVN-944, pyrazofurin, mycophenolate mofetil, azaribine, and brequinar) and six compounds from the NPC library (buparvaquone, valinomycin, narasin, monensin, rotenone, and mubritinib) showed inhibitory activity against rVACV. Notably, the anti-VACV activity of some of the compounds in the ReFRAME library (antimycin A, mycophenolic acid, AVN-944, mycophenolate mofetil, and brequinar) and all the compounds from the NPC library (buparvaquone, valinomycin, narasin, monensin, rotenone, and mubritinib) were confirmed with MPXV, demonstrating their inhibitory activity in vitro against two orthopoxviruses. IMPORTANCE Despite the eradication of smallpox, some orthopoxviruses remain important human pathogens, as exemplified by the recent 2022 monkeypox virus (MPXV) outbreak. Although smallpox vaccines are effective against MPXV, access to those vaccines is limited. In addition, current antiviral treatment against MPXV infections is limited to the use of the FDA-approved drugs tecovirimat and brincidofovir. Thus, there is an urgent need to identify novel antivirals for the treatment of MPXV infection and other potentially zoonotic orthopoxvirus infections. Here, we show that 13 compounds, derived from two different libraries, previously found to inhibit several RNA viruses, also inhibit VACV. Notably, 11 compounds also displayed inhibitory activity against MPXV.
摘要：
历史上，人类的猴痘病毒（MPXV）感染仅限于非洲的流行地区。然而,2022年，全球报告了惊人数量的MPXV病例，带有人与人之间传播的证据。正因为如此,世界卫生组织（WHO）宣布MPXV疫情为国际关注的突发公共卫生事件。MPXV疫苗供应有限,只有两种抗病毒药物，tecovirimat和Brincidofovir，由美国食品和药物管理局（FDA）批准用于治疗天花，目前可用于治疗MPXV感染。这里,我们评估了之前显示的抑制不同RNA病毒的19种化合物抑制正痘病毒感染的能力.我们首先使用表达荧光（mScarlet或绿色荧光蛋白[GFP]）和荧光素酶（Nluc）报告基因的重组牛痘病毒（rVACV）来鉴定具有抗正痘病毒活性的化合物。来自ReFRAME库的七个化合物（抗霉素A，霉酚酸，AVN-944,吡唑呋喃,霉酚酸酯，azaribine,和brequinar）和来自NPC库的六个化合物（bubarvaquone，缬氨酸霉素,Narasin,莫能菌素,鱼藤酮,和mublitinib）显示出对rVACV的抑制活性。值得注意的是,ReFRAME文库中某些化合物的抗VACV活性（抗霉素A，霉酚酸，AVN-944，霉酚酸酯，和brequinar）和NPC文库中的所有化合物（buparvaquone，缬氨酸霉素,Narasin,莫能菌素,鱼藤酮,和mublitinib)被证实与MPXV，证明了它们对两种正痘病毒的体外抑制活性。重要性尽管根除了天花，一些正痘病毒仍然是重要的人类病原体，例如最近的2022年猴痘病毒（MPXV）爆发。虽然天花疫苗对MPXV有效，获得这些疫苗的机会有限。此外,目前针对MPXV感染的抗病毒治疗仅限于使用FDA批准的药物tecovirimat和brincidofovivivir.因此，迫切需要鉴定用于治疗MPXV感染和其他潜在的人畜共患正痘病毒感染的新型抗病毒药物.这里,我们发现13种化合物，来自两个不同的图书馆，以前发现抑制几种RNA病毒，也抑制VACV。值得注意的是,11个化合物也显示出对MPXV的抑制活性。
