Current Topics in Medicinal Chemistry - Volume 13, Issue 23, 2013

Poly(ADP-ribose)polymerases (PARPs) catalyze a post-transcriptional modification of proteins, consisting in the attachment of mono, oligo or poly ADP-ribose units from NAD+ to specific polar residues of target proteins. The scientific interest in members of this superfamily of enzymes is continuously growing since they have been implicated in a range of diseases including stroke, cardiac ischemia, cancer, inflammation and diabetes. Despite some inhibitors of PARP-1, the founder member of the superfamily, have advanced in clinical trials for cancer therapy, and other members of PARPs have recently been proposed as interesting drug targets, challenges exist in understanding the polypharmacology of current PARP inhibitors as well as developing highly selective chemical tools to unravel specific functions of each member of the superfamily. Beginning with an overview on the molecular aspects that affect polypharmacology, in this article we discuss how these may have an impact on PARP research and drug discovery. Then, we review the most selective PARP inhibitors hitherto reported in literature, giving an update on the molecular aspects at the basis of selective PARP inhibitor design. Finally, some outlooks on current issues and future directions in this field of research are also provided.

Human CD38, an ecto-enzyme and a receptor, performs as an independent negative prognostic marker for patients with chronic lymphocytic leukemia (CLL), a hematological malignancy characterized by the accumulation of a population of mature B lymphocytes expressing CD5. Patients with a CD38+ CLL clone display a more aggressive form of the disease with earlier treatment requirements and ultimately shorter overall survival than patients with a CD38- clone. Several lines of evidence indicate that CD38 is not only a diagnostic marker but also a key element in the molecular network regulating disease maintenance and progression. First, CD38 is a receptor that induces proliferation and increases survival of CLL cells. Second, CD38 signals facilitate access of CLL cells to growth-favorable districts. This is achieved by enhancing i) chemotaxis towards CXCL12, ii) integrin-mediated adhesion and iii) matrix metalloprotease synthesis and secretion. Third, blocking monoclonal antibodies targeting CD38 impair CLL homing to spleen and bone marrow in xenograft models. These functions appear to be modulated by frontal interactions with CD31 as well as by lateral associations on the CLL membrane to form a large supramolecular complex similar to the invadosomes of epithelial cells. Our understanding has evolved from considering CD38 as a marker of unfavorable prognosis to recognizing its function as a disease modifier. Studies in the next few years will likely determine whether the molecule can also serve as a target for new therapies, using monoclonal antibodies, inhibitors of the enzymatic activity or both.

Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca2+ mobilizing endogenous compound known to date. Although its Ca2+releasing activity has been demonstrated in many cell types and in response to different extracellular stimuli, several aspects of NAADP signaling are unclear. This overview focuses on the controversial aspects and reviews NAADP´s role as second messenger: endogenous concentrations and its receptor-mediated alterations, metabolism, and potential organelle and ion channel targets. Finally, the role of NAADP as Ca2+ trigger is discussed by reviewing the development of local into global Ca2+ signals evoked by NAADP.

The post-translational modifications of proteins by mono- and poly-ADP-ribosylation involve the cleavage of βNAD+, with the release of its nicotinamide moiety, accompanied by the transfer of a single (mono) or several (poly) ADP-ribose molecules from βNAD+ to a specific amino-acid residue of various cellular proteins. Thus, both mono- and poly-ADP-ribosylation are NAD+-consuming reactions. ADP-ribosylation reactions have been reported to have important roles in the nucleus, and in mitochondrial activity. Distinct subcellular NAD+ pools have been identified, not only in the nucleus and the mitochondria, but also in the endoplasmic reticulum and peroxisomes. Recent reports have shed new light on the correlation between NAD+-dependent ADP-ribosylation reactions and the endoplasmic reticulum. We have demonstrated that ARTD15/PARP16 is a novel mono-ADP-ribosyltransferase with a new intracellular location, as it is associated with the endoplasmic reticulum. The endoplasmic reticulum is a membranous network of tubules, vesicles, and cisternae that are interconnected in the cytoplasm of eukaryotic cells. This intracellular compartment is responsible for many cellular functions, including facilitation of protein folding and assembly, biosynthesis of lipids, storage of intracellular Ca2+, and transport of proteins. ARTD15 might have a role in both the nucleo-cytoplasmic shuttling, through importinβ1 mono-ADP-ribosylation, and in the unfolded protein response through its ability to ADP-ribosylate two components of this pathway: PERK and IRE1. This review summarizes our present knowledge of the enzymes and targets involved in ADP-ribosylation reactions, with special regard to the novel regulatory reactions that occurs at the level of the endoplasmic reticulum, and that can affect the function of this organelle.