Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA.
Department of Ophthalmology and Visual Sciences, Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, USA.
Biomed Pharmacother. 2023 Sep;165:115056. doi: 10.1016/j.biopha.2023.115056. Epub 2023 Jul 4.
Herpes simplex viruses type-1 (HSV-1) and type-2 (HSV-2) are ubiquitous human pathogens causing serious pathologies in the ocular, orofacial and anogenital regions. While current treatments such as nucleoside analogs are effective in most cases, the emergence of drug resistance necessitates the development of newer antivirals with different mechanisms of action. In this regard, BX795, a small molecule inhibitor has shown significant benefit in the treatment of herpesvirus infections previously when dosed topically. However, the efficacy of BX795's systemic dosage remains to be tested. In this study, we evaluated acute and short-term toxicity of orally administered BX795 at a concentration of 400 and 100 mg/kg respectively in mice. This was followed by an evaluation of pharmacokinetics and tissue distribution of BX795 on intravenous and oral administration. Based on these studies, we performed an in vivo antiviral study using murine models of ocular HSV-1 and genital HSV-2 infection. Our results indicate that orally administered BX795 is very well tolerated, had oral bioavailability of 56%, and reached ocular and genital tissues within the first 15 min of dosing. Our studies indicate that BX795 administered orally can significantly reduce herpesvirus replication in the ocular and genital tissue.
单纯疱疹病毒 1 型（HSV-1）和 2 型（HSV-2）是普遍存在的人类病原体，可导致眼部、口腔和生殖器区域的严重病理变化。虽然目前的治疗方法，如核苷类似物，在大多数情况下是有效的，但药物耐药性的出现需要开发具有不同作用机制的新型抗病毒药物。在这方面，小分子抑制剂 BX795 之前在局部给药时已显示出在治疗疱疹病毒感染方面的显著益处。然而，BX795 的全身剂量的疗效仍有待测试。在这项研究中，我们在浓度为 400 和 100mg/kg 的情况下，分别在小鼠中评估了口服 BX795 的急性和短期毒性。随后评估了静脉内和口服给药时 BX795 的药代动力学和组织分布。基于这些研究，我们使用眼部单纯疱疹病毒 1 型和生殖器单纯疱疹病毒 2 型感染的小鼠模型进行了体内抗病毒研究。我们的结果表明，口服给予 BX795 具有很好的耐受性，口服生物利用度为 56%，并在给药后 15 分钟内到达眼部和生殖器组织。我们的研究表明，口服给予 BX795 可以显著减少眼部和生殖器组织中的疱疹病毒复制。
