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. 2024 Apr 18;31(4):658-668.e14.
doi: 10.1016/j.chembiol.2024.02.004. Epub 2024 Mar 19.

PROTAC-mediated degradation of HIV-1 Nef efficiently restores cell-surface CD4 and MHC-I expression and blocks HIV-1 replication

Lori A Emert-Sedlak  1 , Colin M Tice  2 , Haibin Shi  1 , John J Alvarado  1 , Sherry T Shu  1 , Allen B Reitz  2 , Thomas E Smithgall  3
Affiliations

PROTAC-mediated degradation of HIV-1 Nef efficiently restores cell-surface CD4 and MHC-I expression and blocks HIV-1 replication

Lori A Emert-Sedlak et al. Cell Chem Biol. .

Abstract

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.

Keywords: CD4; HIV Nef; HIV-1; MHC-I; PROTACs; antiretroviral drugs; targeted degradation.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Update of

Comment in

  • PROTAC induces HIV-1 Nef degradation.
    Crunkhorn S. Crunkhorn S. Nat Rev Drug Discov. 2024 May;23(5):340. doi: 10.1038/d41573-024-00060-0. Nat Rev Drug Discov. 2024. PMID: 38575781 No abstract available.

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