Anchimerically Activatable Anti-Zika/Dengue ProTides

登革热 (DENV) 和寨卡病毒 (ZIKV) 等虫媒病毒与多种全球流行病有关。 DENV 感染可导致轻度发烧，甚至可能致命的登革休克综合征、登革出血热 和死亡，而 ZIKV 感染可导致先天性小头畸形和自身免疫性疾病的发展 疾病。 DENV 和 ZIKV 疾病的初始临床表现相似，并且已出现共同感染的情况 报道称。最具挑战性的是，DENV 和 ZIKV 已知会共同传播，从而增加了共同感染的可能性， 从而有可能患上严重疾病。因此，由于没有有效的疫苗或治疗形式 对于这两种病毒，开发抗 ZIKV 和抗 DENV 疗法是一项紧迫的未满足的医疗需求。 在过去的十年中，核苷酸前药（称为 ProTides）被发现具有有效的作用。 抗病毒活性。抗丙型肝炎病毒 (HCV) 药物索磷布韦（FDA 于 2013 年批准）是最引人注目的 ProTide 的成功是因为它在联合治疗中的使用可以清除丙型肝炎病毒感染。最近，类似的 ProTide（瑞德西韦）已获得 FDA、日本、欧盟和澳大利亚的批准用于治疗 通过静脉注射治疗严重 SARs-CoV-2 感染。羧酸酯酶-酸酐-HINT1 (CAH) ProTides， 例如索磷布韦和瑞德西韦，利用基于初始酯酶水解的四步活化过程， 羧酸对磷进行亲核攻击并释放苯酚，然后是混合酸酐 化学水解，最后通过 hHINT1 水解氨基磷酸酯。不幸的是，虽然他们可以 静脉给药，由于首过代谢较高，CAH-Protides 作为口服药物的使用受到限制 病毒性肝炎。此外，由于啮齿动物血浆的高羧酸酯酶活性，很难 对啮齿动物和 CAH-ProTides 的转化相关剂量进行临床前研究。 为了解决当前 ProTide 方法的固有问题，我们的团队 设计了另一种 ProTide 方法，我们将其称为非嵌合 HINT1 激活的 proTides （AHA-ProTides）。我们的实验室已经证明 AHA-proTides 可以设计成稳定、 口服生物利用度高，具有细胞渗透性，并且依赖于 HINT 氨基磷酸酯水解。最近，我们 还证明 AHA proTides 可以增强对抗 DENV 的效力 和寨卡病毒。因此，我们建议设计和开发抗DENV和抗ZIKV AHA ProTides 可作为先进的先导化合物，用于潜在治疗 DENV 和寨卡病毒病。

Arboviruses such as, Dengue (DENV) and Zika (ZIKV), have been associated with several global epidemics. DENV infections can result in a mild fever to potentially fatal dengue shock syndrome, dengue hemorrhagic fever and death, while ZIKV infections can result in congenital microcephaly and the development of autoimmune diseases. Initial clinical manifestation of DENV and ZIKV disease are similar and co-infections have been reported. Most challenging, DENV and ZIKV are known to co-circulate, increasing the probability of co-infections, and thus the potential for severe disease. Consequently, since there is no effective vaccine or form of treatment for either virus, the development of anti-ZIKV and anti-DENV therapeutics is an urgent unmet medical need. Over the past decade prodrugs of nucleotides, referred to as ProTides, have been found to have potent antiviral activity. The anti-hepatitis C virus (HCV) drug sofosbuvir (FDA approved 2013) is the most notable ProTide success, since its use in combination therapy can clear Hepatis C virus infections. Recently, a similar ProTide, remdesivir, has been approved by the FDA, Japan, the European Union an Australia for the treatment of severe SARs-CoV-2 infections by intravenous injection. Carboxyesterase-anhydride-HINT1 (CAH) ProTides, such as sofosbuvir and remdesivir, utilize a four step activation process based on initial esterase hydrolysis, carboxylic acid nucleophilic attack at the phosphorous and release of phenol, followed by mixed anhydride chemical hydrolysis, and finally phosphoramidate hydrolysis by hHINT1. Unfortunately, although they can be dosed intravenously, due to high first pass metabolism, CAH-Protides are limited in their use as oral drugs to viral hepatitis. Furthermore, due to the high carboxyesterase activity of rodent plasma, it has been difficult to carry out pre-clinical studies with rodents and translationally relevant dosages of CAH-ProTides. To address the inherent issues surrounding current ProTide approaches, our group has designed an alternative ProTide approach, we refer to as anchimerically HINT1 activated proTides (AHA-ProTides). Our laboratory has demonstrated that AHA-proTides can be designed that are stable, orally bioavailable, cell permeable and dependent on HINT phosphoramidate hydrolysis. Recently, we have also demonstrated that AHA proTides can be prepared with enhanced potency against DENV and ZIKV. Consequently, we propose to the design and develop anti-DENV and anti-ZIKV AHA ProTides that can serve as advanced lead compounds for the potential treatment of both DENV and ZIKV disease.