Department of Pediatrics, University of Alabama School of Medicine, Birmingham AL 35233-1711, USA.
Department of Pediatrics, University of Alabama School of Medicine, Birmingham AL 35233-1711, USA.
Antiviral Res. 2018 Nov;159:153-174. doi: 10.1016/j.antiviral.2018.09.003. Epub 2018 Sep 15.
The recent approval of letermovir marks a new era of therapy for human cytomegalovirus (HCMV) infections, particularly for the prevention of HCMV disease in hematopoietic stem cell transplant recipients. For almost 30 years ganciclovir has been the therapy of choice for these infections and by today's standards this drug exhibits only modest antiviral activity that is often insufficient to completely suppress viral replication, and drives the selection of drug-resistant variants that continue to replicate and contribute to disease. While ganciclovir remains the therapy of choice, additional drugs that inhibit novel molecular targets, such as letermovir, will be required as highly effective combination therapies are developed not only for the treatment of immunocompromised hosts, but also for congenitally infected infants. Sustained efforts, largely in the biotech industry and academia, have identified additional highly active lead compounds that have progressed into clinical studies with varying levels of success and at least two have the potential to be approved in the near future. Some of the new drugs in the pipeline inhibit new molecular targets, remain effective against isolates that have developed resistance to existing therapies, and promise to augment existing therapeutic regimens. Here, we will describe some of the unique features of HCMV biology and discuss their effect on therapeutic needs. Existing drugs will also be discussed and some of the more promising candidates will be reviewed with an emphasis on those progressing through clinical studies. The in vitro and in vivo antiviral activity, spectrum of antiviral activity, and mechanism of action of new compounds will be reviewed to provide an update on potential new therapies for HCMV infections that have progressed significantly in recent years.
最近，来特莫韦的获批标志着人类巨细胞病毒 (HCMV) 感染治疗新时代的到来，尤其可用于预防造血干细胞移植受者的 HCMV 疾病。近 30 年来，更昔洛韦一直是这些感染的首选治疗药物，但按今天的标准，该药的抗病毒活性仅为中等，往往不足以完全抑制病毒复制，并促使耐药变异体的选择，这些变异体继续复制并导致疾病。虽然更昔洛韦仍然是首选治疗药物，但需要额外的抑制新型分子靶标的药物，如来特莫韦，因为正在开发高效的联合疗法，不仅用于治疗免疫功能低下的宿主，还用于治疗先天性感染的婴儿。在生物技术行业和学术界的大力努力下，已经确定了其他具有高度活性的先导化合物，这些化合物已经进入临床研究阶段，取得了不同程度的成功，至少有两种有潜力在不久的将来获得批准。一些新的药物抑制新的分子靶标，对已经对现有疗法产生耐药性的分离株仍然有效，并有望增强现有的治疗方案。在这里，我们将描述 HCMV 生物学的一些独特特征，并讨论它们对治疗需求的影响。还将讨论现有的药物，并对一些更有前途的候选药物进行审查，重点是那些正在进行临床研究的药物。将综述新化合物的体外和体内抗病毒活性、抗病毒活性谱和作用机制，以提供近年来在 HCMV 感染治疗方面取得显著进展的潜在新疗法的最新信息。
