人类免疫缺陷病毒(HIV)
复制(统计)
细胞生物学
降级(电信)
病毒复制
病毒学
生物
计算生物学
病毒
计算机科学
电信
作者
Lori A. Emert‐Sedlak,Colin M. Tice,Haibin Shi,John J. Alvarado,Sherry T. Shu,Allen B. Reitz,Thomas E. Smithgall
标识
DOI:10.1016/j.chembiol.2024.02.004
摘要
The HIV-1 Nef accessory factor enhances the viral life cycle in vivo, promotes immune escape of HIV-infected cells, and represents an attractive antiretroviral drug target. However, Nef lacks enzymatic activity and an active site, complicating traditional occupancy-based drug development. Here we describe the development of proteolysis targeting chimeras (PROTACs) for the targeted degradation of Nef. Nef-binding compounds, based on an existing hydroxypyrazole core, were coupled to ligands for ubiquitin E3 ligases via flexible linkers. The resulting bivalent PROTACs induced formation of a ternary complex between Nef and the cereblon E3 ubiquitin ligase thalidomide-binding domain in vitro and triggered Nef degradation in a T cell expression system. Nef-directed PROTACs efficiently rescued Nef-mediated MHC-I and CD4 downregulation in T cells and suppressed HIV-1 replication in donor PBMCs. Targeted degradation is anticipated to reverse all HIV-1 Nef functions and may help restore adaptive immune responses against HIV-1 reservoir cells in vivo.
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