A Poly-ADP-Ribose Polymer-GCSF Conjugate.

Poly-ADP-ribose (PAR) is a naturally occurring form of polymers synthesized through enzymatic reactions catalyzed by poly(ADP-ribose) polymerases (PARPs). It is known for regulating various important cellular signaling pathways and processes. As a water soluble and biocompatible type of polymer, PAR may hold promise for safe and efficient delivery of therapeutics. To explore the therapeutic potential of PAR polymers, we herein generate PAR polymers conjugated with human granulocyte colony-stimulating factor (GCSF) protein by harnessing human PARP1-catalyzed auto-poly-ADP-ribosylation and a clickable analogue of nicotinamide adenine dinucleotide (NAD). The resulting PAR polymer-based conjugate with multivalent GCSF ligands exhibits a potent cell proliferative activity. Notably, mice treated with a single dose of the PAR polymer-GCSF conjugate show sustained high levels of neutrophil in blood for 11 days, demonstrating excellent efficacy. Functionalized PAR polymers may provide new scaffolds for conjugating with therapeutic proteins or peptides toward improved pharmacological activities.