Antiretroviral Drug Discovery Targeting the HIV-1 Nef Virulence Factor

Abstract

While antiretroviral drugs have transformed the lives of HIV-infected individuals, chronic treatment is required to prevent rebound from viral reservoir cells. People living with HIV also are at higher risk for cardiovascular and neurocognitive complications, as well as cancer. Finding a cure for HIV-1 infection is therefore an essential goal of current AIDS research. This review is focused on the discovery of pharmacological inhibitors of the HIV-1 Nef accessory protein. Nef is well known to enhance HIV-1 infectivity and replication, and to promote immune escape of HIV-infected cells by preventing cell surface MHC-I display of HIV-1 antigens. Recent progress shows that Nef inhibitors not only suppress HIV-1 replication, but also restore sufficient MHC-I to the surface of infected cells to trigger a cytotoxic T lymphocyte response. Combining Nef inhibitors with latency reversal agents and therapeutic vaccines may provide a path to clearance of viral reservoirs.

PROTAC-mediated Degradation of HIV-1 Nef Efficiently Restores Cell-surface CD4 and MHC-I Expression and Blocks HIV-1 Replication

“…Previous studies of these Nef antagonists showed low nanomolar inhibition of HIV-1 replication in primary cells, 23 an effect likely attributed to interference with Nef-activated kinases linked to viral transcription. 6,15 Our findings that these same Nef antagonists, in the context of the PROTACs described here, cause ubiquitylation and degradation of Nef provides strong evidence for their direct interaction with Nef in a cellular context. This observation is also consistent with the ability of these PROTAC analogs to bind directly to recombinant Nef by SPR and to induce formation of ternary complexes with the CRBN thalidomide-binding domain in vitro (Figures 6 and 7).…”

“…Nef is well known to interact with diverse host cell proteins to enhance the viral life cycle, promote immune escape, and support viral persistence. 1,6,15,16,21 Nef lacks an active site and uses multiple structural motifs to recruit cellular signaling partners, complicating traditional occupancy-based antiretroviral drug development. The PROTAC approach detailed here may circumvent this issue, as targeted degradation is likely to antagonize all Nef functions while limiting side effects from non-specific activities.…”

“…11,14 These animal model and HIV patient data establish a central role for Nef in HIV-1 pathogenesis and support the development of Nef antagonists as new therapeutic approach against HIV/AIDS. 15,16…”

“…11,14 These animal model and HIV patient data establish a central role for Nef in HIV-1 pathogenesis and support the development of Nef antagonists as new therapeutic approach against HIV/AIDS. 15,16 Several studies have reported drug discovery efforts targeting HIV-1 Nef. 15,16 One approach involved high-throughput screening of chemical libraries for inhibitors of Nef-dependent activation of a protein kinase partner, the Src-family kinase, Hck.…”

“…15,16 Several studies have reported drug discovery efforts targeting HIV-1 Nef. 15,16 One approach involved high-throughput screening of chemical libraries for inhibitors of Nef-dependent activation of a protein kinase partner, the Src-family kinase, Hck. 17,18 This screen identified a unique Nef-binding compound based on a hydroxypyrazole core that inhibited Nef-dependent enhancement of HIV-1 infectivity, replication, and partially reversed Nef-mediated MHC-I downregulation.…”