An X-Chem DEL-derived compound enabled this work that explores a novel mechanistic strategy for HIV therapeutics.

DCAF1 is a donut-shaped WD40 repeat protein and a substrate receptor of two distinct E3 ligases. In HIV-1 infection, the viral protein Vpr binds to the top surface of DCAF1, changes its substrate specificity to degrade human proteins involved in antiviral activities, enabling HIV-1 to replicate. The authors hypothesized that artificial top-to-top self-dimerization of DCAF1 could result in DCAF1 loss-of-function and blocking of the Vpr-DCAF1 interaction. Using DCAF1inhibitors previously discovered in an X-Chem collaboration, they designed and synthesized seven compounds termed SDIPTACs (Self-Dimerization Induced Proximity Targeting Chimeras), which artificially induce DCAF1 self-dimerization through the Vpr interaction surface. SDIPTACs C8 and C9 inhibited Vpr-dependent HIV replication in CD4+ T cells. Biophysical data and crystal structures of four DCAF1-SDIPTAC-DCAF1 ternary complexes revealed further details on DCAF1-DCAF1 complex stability, conformation, and their contribution to compound efficacy. SDIPTACs represent a mechanistically distinct strategy with potential for the development of future therapeutics for HIV infection and other diseases.