A single antiviral to treat multiple opportunistic infections

目前的标准抗病毒治疗方案依赖于具有固有责任的直接作用抗病毒药物（DAA）。 DAA通常仅对一种病毒或密切相关的病毒家族具有活性。因为病毒蛋白质 有针对性的，病毒可以很容易地产生耐药性突变。为了解决DAA的缺点，FORGE Life 科学正在开发宿主靶向抗病毒药物（HTAs）。HTA有可能阻止多种 不同的病毒由于靶向的是宿主细胞蛋白质，因此病毒不太可能进化出耐药性。 具体来说，FORGE正在开发针对人类sirtuin蛋白的小分子药物。Sirtuins是一个家庭 七种蛋白质脱酰基酶，调节许多对病毒复制至关重要的细胞过程。这项建议 寻求开发一种调节沉默调节蛋白的药物， 机会性病毒在免疫抑制移植患者中引起危及生命的疾病。最初 该计划的重点是人类巨细胞病毒（HCMV）。在第一阶段，一个化学系列的无竞争力的sirtuin 2 （SIRT 2）抑制剂被开发，其在培养的人细胞中阻断HCMV子代的产生， 比标准治疗药物更昔洛韦更有效引人注目的是，这些SIRT 2抑制剂不仅影响HCMV， 还抑制甲型和B型流感病毒、B型和C型肝炎病毒以及多瘤病毒、BKV和JCV的生长。 该系列化合物的抗病毒活性与其构效关系密切， 生物利用度和良好的耐受性。抗HCMV活性的体内验证在 携带人类肺组织植入物的免疫抑制小鼠。本申请建议将程序 SBIR II期，以优化进入临床前开发的候选开发。 将追求三个目标。(1)支持最近批准的DAA莱特莫韦开发的小鼠模型 将适用于SIRT 2抑制剂。该模型允许接种人成纤维细胞的HCMV感染， 将明胶海绵植入免疫缺陷的SCID小鼠体内。(2)药物化学运动将完善 目前的SIRT 2抑制剂可以提高Gelfoam/SCID小鼠的抗HCMV活性，其靶点是 达到相当于或优于口服剂量的缬更昔洛韦和莱特莫韦的治疗指数。所选 开发候选物还将满足体外ADME和药学标准，包括 最小化药物-药物相互作用，用于移植患者给药。(3)化合物显示 将验证在Gelfoam/SCID小鼠模型中提供高屏障的足够功效 获得性病毒耐药性，并与现有的直接作用的抗病毒药协同作用。泛病毒特征将 扩展到多种机会性病毒。这个项目有可能产生一个范式转变， 引入广谱抗病毒药物，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.