pan-DDR DNA decoy-cholesterol conjugate VIO-01

A pan-DNA damage response (DDR) DNA decoy linked to a cholesterol molecule, with potential immunomodulatory and antineoplastic activities. Upon administration of pan-DDR DNA decoy-cholesterol conjugate VIO-01, the cholesterol moiety enables tumoral and nuclear uptake of the DNA, and mimics DNA double-strand breaks (DSBs) inside the tumor cells. This triggers false DNA break signals, binding to and activating DNA repair proteins including poly(ADP-ribose) polymerase (PARP) 1, KU70/80, MRN complex and MSH2/MSH3. This prevents the recruitment of these repair proteins at the actual damage site and inhibits various DNA DSB repair pathways. This promotes genetic instability and enhances the accumulation of single and double strand DNA breaks, ultimately leading to apoptosis of tumor cells. VIO-01 also triggers the activation of the stimulator of interferon genes protein (STING; transmembrane protein 173; TMEM173) pathway in immune cells in the tumor microenvironment (TME). This leads to the production of pro-inflammatory cytokines, including interferons (IFNs), enhances the cross-presentation of tumor-associated antigens (TAAs) by dendritic cells (DCs), and induces a cytotoxic T-lymphocyte (CTL)-mediated immune response against cancer cells. PARP1 catalyzes post-translational ADP-ribosylation of nuclear proteins that signal and recruit other proteins to repair damaged DNA and plays a key role in the repair of single strand DNA (ssDNA) breaks and DSBs. STING, a transmembrane protein that activates immune cells in the TME, plays a key role in the activation of the innate immune system.