Enzymatic and Chemical Synthesis for ADP-Ribosylation Using NAD+ as Building Blocks: New Concerns in Reaction Discovery and Design.

Nicotinamide adenine dinucleotide (NAD+), as an endogenous donor for ADP-ribosylation, can modify DNA, RNA, and proteins, thereby participating in the regulation of the functions of these biomacromolecules. NAD+ serves as a reactant in both enzymatic and chemical synthesis. By employing a well-designed reaction process, the synthetic route can be significantly streamlined, enabling the preparation of structurally complex bioactive molecules in a step-saving and highly effective manner. This article reviews the latest research progress in this field. In the field of enzymatic synthesis, a strategy based on the HPF1/PARP1 complex has been developed. Earlier study shows that the recombinant HPF1/PARP1 complex can ADP-ribosylate a variety of substrates in vitro. In the field of chemical synthesis, the focus is on ionic liquid-mediated ADP-ribosylation reactions with controllable α/β configurations of products. These reactions help prepare biologically active ADP-ribosylated (ADPr) peptides from NAD+ and commercially available peptides. In addition, this article also outlines the applications of functional NAD+ derivatives in enzyme activity analysis and inhibitor development and discusses the challenges faced in this field, such as bio-compatible reaction conditions, synthesis for precise structural control, and structure-activity relationships between stereochemistry and biological functions of more ADPr derivatives.