In Vitro and In Vivo Activity, Tolerability, and Mechanism of Action of BX795 as an Antiviral against Herpes Simplex Virus 2 Genital Infection
In Vitro and In Vivo Activity, Tolerability, and Mechanism of Action of BX795 as an Antiviral against Herpes Simplex Virus 2 Genital Infection
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DOI：
10.1128/aac.00245-20
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发表时间：
2020-09-01
影响因子：
4.9
通讯作者：
Shukla, Deepak
中科院分区：
文献类型：
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作者：
Hopkins, James;Yadavalli, Tejabhiram;Shukla, Deepak
单纯疱疹病毒2型（HSV-2）在肛门生殖器区域引起复发性病变，可能通过性接触传播。核苷类似物，如阿昔洛韦（ACV），目前在临床上用于抑制这种感染。然而，在某些情况下，由于出现对这些药物的耐药性，已观察到疗效降低。在我们之前的研究中，我们报道了一种新的抗hsv -1小分子BX795的发现，它最初被用作tank结合激酶1 （TBK1）的抑制剂。在本研究中，我们报道了BX795在体外10 μ M和体内50 μ M条件下对阴道上皮细胞HSV-2感染的抗病毒作用。我们发现BX795在阴道上皮细胞中具有高达80 μ m浓度的耐受性。我们的研究还揭示了BX795抗病毒活性的作用机制源于通过抑制蛋白激酶B磷酸化来减少病毒蛋白翻译。最后，通过小鼠阴道感染模型，我们发现使用50 μ M BX795局部治疗具有良好的耐受性和有效的控制HSV-2复制。
Herpes simplex virus type 2 (HSV-2) causes recurrent lesions in the anogenital area that may be transmitted through sexual encounters. Nucleoside analogs, such as acyclovir (ACV), are currently prescribed clinically to curb this infection. However, in some cases, reduced efficacy has been observed due to the emergence of resistance against these drugs. In our previous study, we reported the discovery of a novel anti-HSV-1 small molecule, BX795, which was originally used as an inhibitor of TANK-binding kinase 1 (TBK1). In this study, we report the antiviral efficacy of BX795 on HSV-2 infection in vaginal epithelial cells in vitro at 10 mu M and in vivo at 50 mu M. Additionally, through biochemical assays in vitro and histopathology in vivo, we show the tolerability of BX795 in vaginal epithelial cells at concentrations as high as 80 mu M. Our investigations also revealed that the mechanism of action of BX795 anti-viral activity stems from the reduction of viral protein translation via inhibition of protein kinase B phosphorylation. Finally, using a murine model of vaginal infection, we show that topical therapy using 50 mu M BX795 is well tolerated and efficacious in controlling HSV-2 replication.