NAD Analogs in Aid of Chemical Biology and Medicinal Chemistry

Abstract

Nicotinamide adenine dinucleotide (NAD) serves as an essential redox co-factor and mediator of multiple biological processes. Besides its well-established role in electron transfer reactions, NAD serves as a substrate for other biotransformations, which, at the molecular level, can be classified as protein post-translational modifications (protein deacylation, mono-, and polyADP-ribosylation) and formation of signaling molecules (e.g., cyclic ADP ribose). These biochemical reactions control many crucial biological processes, such as cellular signaling and recognition, DNA repair and epigenetic modifications, stress response, immune response, aging and senescence, and many others. However, the links between the biological effects and underlying molecular processes are often poorly understood. Moreover, NAD has recently been found to tag the 5′-ends of some cellular RNAs, but the function of these NAD-capped RNAs remains largely unrevealed. Synthetic NAD analogs are invaluable molecular tools to detect, monitor, structurally investigate, and modulate activity of NAD-related enzymes and biological processes in order to aid their deeper understanding. Here, we review the recent advances in the design and development of NAD analogs as probes for various cellular NAD-related enzymes, enzymatic inhibitors with anticancer or antimicrobial therapeutic potential, and other NAD-related chemical biology tools. We focus on research papers published within the last 10 years.

A molecular toolbox for ADP-ribosyl binding proteins

“…While we could use the GAP-tag to site-specifically label proteins with ADP-ribose, we sought to demonstrate that this system could be extended with NAD + analogs to introduce various chemical groups to the C-terminus of proteins. Many NAD + analogs already exist and are commercially available such as biotinylated, fluorescent and click-chemistry ready NAD + analogs (Depaix and Kowalska, 2019). We first tested the modification of GAP-tagged YFP with 6-biotin-17-NAD + and confirmed that this NAD + analog serves as substrate for PT-based modification of the GAP-tag (Figure 3a).…”

The role of NAD and NAD precursors on longevity and lifespan modulation in the budding yeast, Saccharomyces cerevisiae

“…Pellagra is a dermatitis, diarrhea, and dementia related disease that occurs as a result of dietary deficiency of niacin and vitamin B3 compounds (Orlandi et al 2017 ; Sahar et al 2011 ). There have been elaborate studies on how this molecule relates to aging (Braidy and Liu 2020 ; Yoshino et al 2018 ; Depaix and Kowalska 2019 ), thus positioning it as a major universally conserved age-dependent biomolecule. Upon decline of NAD, cell aging ensues owing to the damaging effects of accumulated toxic molecules.…”

Mono(ADP-ribosyl)ation Enzymes and NAD+ Metabolism: A Focus on Diseases and Therapeutic Perspectives

“…ARTD11 targets NXF1 (an mRNA-binding protein involved in the nucleocytoplasmic shuttle) and NUP98, while modification of NAGK is dependent on the WWE domain present in the ARTD11/PARP11 enzyme [ 119 , 120 ]. ITK7, a quinazolin-4(3H)-one scaffold with propynyl in R1 and pyrimidine in R2 substitutions, showed high specificity toward ARTD11, whose activity towards nuclear pore complex proteins leads ARTD11 to dissociate from the nuclear envelope [ 121 ].…”

“…The nuclear transport protein RAN is also an ARTD10 substrate [ 87 ]. WRIP1 protein was used as a dual ARTD10/ARTD11 MARylation target in cell extracts [ 119 , 120 ].…”