didehydro-Cortistatin A

**Didehydro-Cortistatin A (dCA)** is a synthetic small molecule analog of the natural steroidal alkaloid cortistatin A, featuring a complex polycyclic structure with an isoquinoline side chain and molecular formula C30H34N2O3. It primarily functions as a potent inhibitor of HIV-1 replication by specifically binding to the unstructured basic domain of the HIV-1 Tat protein, stabilizing a transient conformer that disrupts Tat-TAR RNA interaction, inhibits transcriptional elongation, blocks RNA polymerase II recruitment to the viral long terminal repeat (LTR) promoter, and prevents viral reactivation from latent reservoirs. This "block-and-lock" mechanism promotes persistent HIV latency, reduces residual viremia, and delays viral rebound even after treatment cessation, with demonstrated efficacy in primary T cells from ART-suppressed patients (92.3% reduction in reactivation) and humanized mouse models. Additional effects include inhibiting Tat-mediated neuroinflammation by suppressing cytokines (IL-1β, TNF-α, MCP-1) and extracellular Tat uptake by glial cells, potentially mitigating HIV-associated neurocognitive disorders (HAND); it also inhibits CDK8/19 at higher concentrations but this is secondary to Tat inhibition for anti-HIV activity.[1][2][3][4][5][7][12]

Other names

Didehydrocortistatin AD16 cortistatin AD-16 cortistatin AD 16 cortistatin A