Biochemistry and Molecular Biology, Molecular Epigenetics, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Med Res Rev. 2020 May;40(3):881-908. doi: 10.1002/med.21638. Epub 2019 Oct 13.
The latency phenomenon produced by human immunodeficiency virus (HIV-1) prevents viral clearance by current therapies, and consequently development of a cure for HIV-1 disease represents a formidable challenge. Research over the past decade has resulted in identification of small molecules that are capable of exposing HIV-1 latent reservoirs, by reactivation of viral transcription, which is intended to render these infected cells sensitive to elimination by immune defense recognition or apoptosis. Molecules with this capability, known as latency-reversing agents (LRAs) could lead to realization of proposed HIV-1 cure strategies collectively termed "shock and kill," which are intended to eliminate the latently infected population by forced reactivation of virus replication in combination with additional interventions that enhance killing by the immune system or virus-mediated apoptosis. Here, we review efforts to discover novel LRAs via low- and high-throughput small molecule screens, and summarize characteristics and biochemical properties of chemical structures with this activity. We expect this analysis will provide insight toward further research into optimized designs for new classes of more potent LRAs.
人类免疫缺陷病毒 (HIV-1) 产生的潜伏现象阻止了当前疗法清除病毒，因此，开发 HIV-1 疾病的治愈方法是一项艰巨的挑战。过去十年的研究已经确定了一些小分子，这些小分子能够通过重新激活病毒转录来暴露 HIV-1 的潜伏库，从而使这些感染细胞对免疫防御识别或细胞凋亡的清除敏感。具有这种能力的分子，称为潜伏逆转剂 (LRA)，可能会导致提出的 HIV-1 治愈策略的实现，这些策略统称为“冲击和杀伤”，旨在通过强制重新激活病毒复制，并结合增强免疫系统杀伤或病毒介导的细胞凋亡的额外干预措施，来消除潜伏感染人群。在这里，我们通过低和高通量小分子筛选来回顾发现新型 LRA 的努力，并总结具有这种活性的化学结构的特征和生化性质。我们希望这项分析将为进一步研究优化设计新型更有效的 LRA 提供思路。
