Human cytomegalovirus (HCMV) infections are widespread among the human population. Infection is persistent and mostly asymptomatic, except in immunocompromised individuals, particularly transplant patients, where significant morbidity and mortality can occur. Currently approved drugs for treating HCMV-related disease [including ganciclovir (GCV), valganciclovir (VGCV), cidofovir (CDV) and foscarnet (FOS)] all target the viral DNA polymerase and suffer from dose-limiting toxicity and resistance issues. The most recently approved drug, letermovir (LMV), was approved only for prophylaxis in adult HCMV-seropositive stem cell transplant recipients. Although LMV is highly potent, high-grade resistance mutations in the terminase gene were shown to readily emerge in vitro and in treated patients. Therefore, there is a need for new drugs that can be used for combinatorial therapeutic and/or prophylactic regimens to counteract the emergence of resistant mutants. Filociclovir (FCV), also known as cyclopropavir or MBX-400, is a methylenecyclopropane nucleoside analog, which has successfully completed Phase I safety studies, and is now entering Phase II clinical efficacy studies for the treatment of HCMV-related disease in transplant patients. FCV is 10-fold more active than GCV against HCMV in vitro, and has activity against all human herpesviruses except HSV-1 and HSV-2. Recently, FCV was also shown to be highly potent against human adenoviruses. This activity spectrum suggests that FCV could be used to treat/prevent infection with several viruses that pose significant risk to transplant patients. The active triphosphate form of FCV (FCV-TP) reaches higher peak levels than GCV-TP in HCMV-infected cells, and exhibits about 10-fold higher affinity to HCMV DNA polymerase UL54. Furthermore, FCV was shown to retain activity against a panel of GCV-resistant HCMV isolates, suggesting that it could be a useful alternative therapy for treating patients infected with some GCV-resistant HCMV strains. This review summarizes the early discovery work of FCV and highlights the recent advances in the continued development of this clinical candidate.

中文翻译：

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filociclovir的发现和开发，用于预防和治疗人类巨细胞病毒相关疾病。

人类巨细胞病毒（HCMV）感染在人群中很普遍。感染是持续性的，并且大多数是无症状的，除了免疫功能低下的个体，特别是移植患者，在这些患者中可能会发生高发病率和死亡率。当前批准的用于治疗HCMV相关疾病的药物[包括更昔洛韦（GCV），缬更昔洛韦（VGCV），西多福韦（CDV）和膦甲酸（FOS）]均以病毒DNA聚合酶为靶标，并存在剂量限制的毒性和耐药性问题。最新批准的药物letermovir（LMV）仅批准用于成人HCMV血清反应阳性干细胞移植受者的预防。尽管LMV具有很强的效力，但在体外和接受治疗的患者中，Terminase基因中的高水平耐药性突变很容易出现。因此，需要可用于组合治疗和/或预防方案以抵消抗性突变体的出现的新药。Filociclovir（FCV），也称为环丙环孕烷或MBX-400，是一种亚甲基环丙烷核苷类似物，已成功完成I期安全性研究，目前正进入II期临床疗效研究，以治疗移植患者的HCMV相关疾病。FCV在体外对HCMV的活性比GCV高10倍，并且对除HSV-1和HSV-2之外的所有人类疱疹病毒均具有活性。最近，FCV还显示出对人腺病毒的强效作用。该活性谱表明，FCV可用于治疗/预防几种对移植患者构成重大风险的病毒的感染。FCV的活性三磷酸形式（FCV-TP）在HCMV感染的细胞中比GCV-TP达到更高的峰值水平，并且对HCMV DNA聚合酶UL54的亲和力高出约10倍。此外，显示FCV保留了针对一组抗GCV的HCMV分离株的活性，这表明FCV可能是治疗某些抗GCV的HCMV菌株感染患者的有用替代疗法。这篇综述总结了FCV的早期发现工作，并重点介绍了该临床候选药物的持续开发中的最新进展。这表明它可能是治疗感染了某些抗GCV的HCMV菌株的患者的有用替代疗法。这篇综述总结了FCV的早期发现工作，并重点介绍了该临床候选药物的持续开发中的最新进展。这表明它可能是治疗感染了某些抗GCV的HCMV菌株的患者的有用替代疗法。这篇综述总结了FCV的早期发现工作，并重点介绍了该临床候选药物的持续开发中的最新进展。