A single antiviral to treat multiple opportunistic infections

目前的标准护理抗病毒疗法依赖于具有固有责任的直接作用抗病毒药物(DAA)。 DaaS通常只对一种病毒或一组密切相关的病毒起作用。因为病毒蛋白是 如果有针对性，病毒很容易产生抗药性突变。解决DAA的缺点，打造生活 科学正在开发针对宿主的抗病毒药物(HTA)。HTA有可能阻止多个 不同的病毒。由于以宿主细胞蛋白为靶标，病毒产生抗药性的可能性要小得多。 具体地说，Forge正在开发针对人类sirtuin蛋白的小分子药物。先生们是一个大家庭 七种蛋白质脱酰酶中的一种，它们调节许多对病毒复制至关重要的细胞过程。这项建议 寻求开发一种调节sirtuin的药物，该药物对多种不同的 在免疫抑制的移植患者中引起危及生命的疾病的机会性病毒。最初， 该计划的重点是人类巨细胞病毒(HCMV)。在第一阶段，非竞争性sirtuin 2的化学系列 (SIRT2)抑制剂被开发出来，可以更多地阻止培养的人类细胞产生巨细胞病毒后代 比标准护理更昔洛韦更有效。引人注目的是，这些SIRT2抑制剂不仅影响HCMV，而且它们 对甲型和乙型流感病毒、乙型和丙型肝炎病毒以及多瘤病毒、BKV和JCV的生长也有抑制作用。 该化合物系列显示出结构活性与抗病毒效力的关系，口服效果极佳 生物利用度和良好的小鼠耐受性。抗人巨细胞病毒活性的体内验证是在 携带人肺组织植入物的免疫抑制小鼠。此应用程序建议将程序 期待进入SBIR第二阶段，以优化进入临床前开发的候选开发。 我们将追求三个目标。(1)支持新近批准的DAA letermov发展的小鼠模型 将被改装成与SIRT2抑制剂一起使用。该模型允许人巨细胞病毒感染种植的人成纤维细胞。 到植入免疫缺陷SCID小鼠体内的明胶海绵植入物。(2)药物化学活动将提炼 目前领先的SIRT2抑制剂可提高明胶海绵/SCID小鼠的抗HCMV活性，靶向为 达到与口服伐更昔洛韦和来特莫韦相当或更好的治疗指数。选定的 开发候选药物还将满足体外ADME和制药标准，包括 最大限度地减少药物与药物的相互作用，用于移植患者的给药。(3)示范化合物 在明胶海绵/SCID小鼠模型中，关于提供高屏障方面的足够疗效将得到验证 以获得病毒耐药性，并与现有的直接作用抗病毒药物协同作用。泛病毒档案将会 扩展到多个机会性病毒。这个项目有可能带来范式的转变， 推出广谱抗病毒药物，解决病毒耐药性问题。

Current standard-of-care antiviral regimens rely on direct-acting antivirals (DAAs) possessing inherent liabilities. DAAs are generally active against only one virus or a closely related, family of viruses. Because a viral protein is targeted, the virus can readily develop resistance mutations. To address the shortcomings of DAAs, FORGE Life Science is developing host-targeted antivirals (HTAs). HTAs have the potential to block the growth of multiple different viruses. Since a host-cell protein is targeted, viruses are much less likely to evolve drug resistance. Specifically, FORGE is developing small molecule drugs that target human sirtuin proteins. Sirtuins are a family of seven protein-deacylases that modulate many cellular processes critical for virus replication. This proposal seeks to develop a sirtuin-modulating drug that is simultaneously effective against multiple different opportunistic viruses causing life-threatening disease in immunosuppressed transplant patients. Initially, the program is focused on human cytomegalovirus (HCMV). In Phase 1, a chemical series of uncompetitive sirtuin 2 (SIRT2) inhibitors was developed that block the production of HCMV progeny in cultured human cells more potently than standard-of-care, ganciclovir. Strikingly, these SIRT2 inhibitors not only affect HCMV, but they also inhibited the growth of influenza A and B, hepatitis B and C viruses, and the polyomaviruses, BKV and JCV. The compound series demonstrates structure activity relationship to antiviral potency, excellent oral bioavailability, and good tolerability in mice. In vivo validation of anti-HCMV activity was achieved in immunosuppressed mice carrying human lung-tissue implants. This application proposes to move the program forward to SBIR Phase II to optimize a development candidate for progression into preclinical development. Three aims will be pursued. (1) A mouse model supporting development of recently approved DAA letermovir will be adapted for use with SIRT2 inhibitors. This model allows for HCMV infection of human fibroblasts seeded to a Gelfoam implant placed into immunodeficient SCID mice. (2) A medicinal chemistry campaign will refine the current lead SIRT2 inhibitor to improve anti-HCMV activity in the Gelfoam/SCID mouse with a target to achieve a therapeutic index equivalent or better than oral-dosing valganciclovir and letermovir. The selected development candidate will additionally satisfy in vitro ADME and pharmaceutical criteria, including minimizing drug-drug interactions, for administration to transplant patients. (3) Compounds demonstrating sufficient efficacy in the Gelfoam/SCID mouse model will be validated with respect to providing a high barrier to acquired viral drug-resistance and to synergize with existing direct-acting antivirals. The pan-viral profile will be expanded to multiple opportunistic viruses. This project has the potential to produce a paradigm shift, introducing broad-spectrum antivirals that solve the problem of viral resistance.