Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, USA.
Perelman School of Medicine, University of Pennsylvania, USA.
Antiviral Res. 2023 Mar;211:105520. doi: 10.1016/j.antiviral.2022.105520. Epub 2023 Jan 2.
Molluscum contagiosum (MC) is an infectious disease that occurs only in humans with a tropism that is narrowly restricted to the outermost epidermal layer of the skin. Molluscum contagiosum virus (MCV) is the causative agent of MC which produces skin lesions that can persist for months to several years. MCV is efficiently transmitted by direct physical contact or by indirect contact with fomites. MC is most prevalent in children and immune compromised patients. The failure to develop a drug that targets MCV replication has been hampered for decades by the inability to propagate MCV in cell culture. To address this dilemma, we recently engineered a surrogate poxvirus expressing the MCV processivity factor (mD4) as the drug target. The mD4 protein is essential for viral replication by keeping the viral polymerase tethered to the DNA template. In this study we have designed and synthesized a lead compound (7269) that is able to prevent mD4 dependent processive DNA synthesis in vitro (IC = 6.8 μM) and effectively inhibit propagation of the mD4-VV surrogate virus in BSC-1 cells (EC = 13.2 μM) with negligible cytotoxicity. In human liver microsomes, 7269 was shown to be stable for almost 2 h. When tested for penetration into human cadaver skin in a formulated gel, the level of 7269 in the epidermal layer was nearly 100 times the concentration (EC) needed to inhibit propagation of the mD4-VV surrogate virus in BSC-1 cells. The gel formulated 7269 was scored as a non-irritant on skin and shown to have a shelf-life that was completely stable after several months. In summary, 7269 is a potential Lead for becoming the first MCV anti-viral compound to treat MC and thereby, addresses this unmet medical need that has persisted for many decades.
传染性软疣（MC）是一种仅在人类中发生的传染病，其趋向性严格局限于皮肤的最外层表皮层。传染性软疣病毒（MCV）是导致 MC 的病原体，它会产生可持续数月至数年的皮肤损伤。MCV 通过直接身体接触或间接接触污染物有效地传播。MC 在儿童和免疫功能低下的患者中最为常见。几十年来，由于无法在细胞培养中繁殖 MCV，因此未能开发出针对 MCV 复制的药物。为了解决这个困境，我们最近设计了一种表达 MCV 持续因子（mD4）的替代痘病毒作为药物靶点。mD4 蛋白通过将病毒聚合酶固定在 DNA 模板上，对于病毒复制至关重要。在这项研究中，我们设计并合成了一种先导化合物（7269），它能够在体外阻止 mD4 依赖性连续 DNA 合成（IC=6.8μM），并有效地抑制 BSC-1 细胞中 mD4-VV 替代病毒的繁殖（EC=13.2μM），同时具有可忽略的细胞毒性。在人肝微粒体中，7269 几乎稳定了将近 2 小时。当在配方凝胶中测试其穿透人体尸体皮肤的能力时，7269 在表皮层中的水平几乎是抑制 BSC-1 细胞中 mD4-VV 替代病毒繁殖所需浓度（EC）的 100 倍。配方为 7269 的凝胶在皮肤上被评为非刺激性，并显示出在几个月后完全稳定的保质期。总之，7269 是成为第一种治疗 MC 的 MCV 抗病毒化合物的潜在先导化合物，从而解决了这一持续了几十年的未满足的医疗需求。
