Biomedical Biotechnology Research Unit (BioBRU), Department of Biochemistry and Microbiology, Rhodes University, Grahamstown, South Africa.
School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.
Antiviral Res. 2024 Oct;230:105990. doi: 10.1016/j.antiviral.2024.105990. Epub 2024 Aug 16.
Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent for primary effusion lymphoma (PEL), multicentric Castleman's disease (MCD) and Kaposi's sarcoma (KS). KSHV is one of the oncoviruses that contribute to 1.5 million new infection-related cancer cases annually. Currently, there are no targeted therapies for KSHV-associated diseases. Through the development of a medium-throughput phenotype-based ELISA screening platform based on KSHV ORF57 protein detection, we screened the Medicines for Malaria Venture (MMV) Pandemic Response Box for non-cytotoxic inhibitors of KSHV lytic replication. MMV1645152 was identified as a promising inhibitor of KSHV lytic replication, suppressing KSHV immediate-early and late lytic gene expression and blocking the production of infectious KSHV virion particles at non-cytotoxic concentrations in cell line models of KSHV infection with or without EBV coinfection. MMV1645152 is a promising hit compound for the development of future therapeutic agents against KSHV-associated malignancies.
卡波氏肉瘤相关疱疹病毒（KSHV）是原发性渗出性淋巴瘤（PEL）、多发性中心性 Castleman 病（MCD）和卡波氏肉瘤（KS）的病原体。KSHV 是导致每年新增 150 万与感染相关癌症病例的致癌病毒之一。目前，尚无针对 KSHV 相关疾病的靶向疗法。通过开发基于 KSHV ORF57 蛋白检测的高通量表型筛选 ELISA 筛选平台，我们从疟疾药物发现基金会（MMV）大流行应对盒中筛选出非细胞毒性的 KSHV 裂解复制抑制剂。MMV1645152 被鉴定为一种有前途的 KSHV 裂解复制抑制剂，在存在或不存在 EBV 共感染的 KSHV 感染细胞系模型中，以非细胞毒性浓度抑制 KSHV 即刻早期和晚期裂解基因表达，并阻断感染性 KSHV 病毒粒子的产生。MMV1645152 是一种很有前途的候选化合物，可用于开发针对 KSHV 相关恶性肿瘤的未来治疗药物。
