Division of Medicinal Chemistry, Department of Chemistry and Pharmacy, University of Erlangen-Nürnberg (FAU), 91058 Erlangen, Germany.
Institute for Clinical and Molecular Virology, University of Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany.
Viruses. 2021 Mar 12;13(3):471. doi: 10.3390/v13030471.
Nuclear egress is an essential process in the replication of human cytomegalovirus (HCMV), as it enables the migration of newly formed viral capsids from the nucleus into the cytoplasm. Inhibition of the HCMV core nuclear egress complex (core NEC), composed of viral proteins pUL50 and pUL53, has been proposed as a potential new target for the treatment of HCMV infection and disease. Here, we present a new type of small molecule inhibitors of HCMV core NEC formation, which inhibit the pUL50-pUL53 interaction at nanomolar concentrations. These inhibitors, i.e., verteporfin and merbromin, were identified through the screening of the Prestwick Chemical Library of approved drug compounds. The inhibitory effect of merbromin is both compound- and target-specific, as no inhibition was seen for other mercury-organic compounds. Furthermore, merbromin does not inhibit an unrelated protein-protein interaction either. More importantly, merbromin was found to inhibit HCMV infection of cells in three different assays, as well as to disrupt HCMV NEC nuclear rim formation. Thus, while not being an ideal drug candidate by itself, merbromin may serve as a blueprint for small molecules with high HCMV core NEC inhibitory potential, as candidates for novel anti-herpesviral drugs.
核输出是人类巨细胞病毒（HCMV）复制的一个基本过程，因为它使新形成的病毒衣壳从细胞核迁移到细胞质。抑制 HCMV 核心核输出复合物（core NEC），由病毒蛋白 pUL50 和 pUL53 组成，已被提议作为治疗 HCMV 感染和疾病的潜在新靶标。在这里，我们提出了一种新型的 HCMV core NEC 形成的小分子抑制剂，它以纳摩尔浓度抑制 pUL50-pUL53 相互作用。这些抑制剂，即维替泊芬和汞溴红，是通过筛选已批准药物化合物的 Prestwick 化学库发现的。汞溴红的抑制作用具有化合物和靶标特异性，因为其他汞有机化合物没有抑制作用。此外，汞溴红也不抑制不相关的蛋白质-蛋白质相互作用。更重要的是，发现汞溴红在三种不同的测定中抑制细胞中的 HCMV 感染，以及破坏 HCMV NEC 核边缘形成。因此，虽然汞溴红本身并不是一种理想的药物候选物，但它可以作为具有高 HCMV core NEC 抑制潜力的小分子的蓝图，作为新型抗疱疹病毒药物的候选物。
