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NAD Metabolism and Related Drug Compounds

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 7547

Special Issue Editors


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Guest Editor
Chemistry Interdisciplinary Project (CHIP), School of Pharmacy, University of Camerino, Via Madonna delle Carceri, 62032 Camerino, Italy
Interests: medicinal chemistry; small-molecules; essential oils; naturally-occurring compounds; NAD-dependent enzymes; plant secondary metabolites; bioactive-active fractionation; phytochemicals; ethnopharmacology; biological activity of natural compounds
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Guest Editor
Department of Clinical Sciences, Section of Biochemistry, Polytechnic University of Marche, 60131 Ancona, Italy
Interests: niacin; vitamin B3; NAD(P); enzymology; metabolism; Wallerian degeneration; neurodegeneration

Special Issue Information

Dear Colleagues,

Nicotinamide adenine dinucleotide (NAD) is a long-known universal coenzyme for cellular redox reactions that takes metabolic origin from the B3 vitamin “niacin”; in recent times, it has also been found to participate as a consumed substrate in an increasingly diverse range of cellular reactions and processes, including signal transduction, DNA repair, and post-translational protein modifications. Because of that, in recent years, medicinal chemists have become interested in the therapeutic potential of molecules affecting the interactions of NAD with NAD-dependent enzymes. Further, enzymes involved in de novo biosynthesis, salvage pathways, and downstream utilization of NAD have been extensively investigated and implicated in a wide variety of diseases. These studies have bolstered NAD-based therapeutics as a new avenue for discovering and developing novel treatments for medical conditions, such as cancer, neurodegeneration, aging, etc. Industrial and academic groups have produced structurally diverse molecules, which target NAD metabolic pathways, with some candidates advancing into clinical trials. However, further intensive structural, biological, and medical studies are needed to facilitate the design and evaluation of new generations of NAD-based therapeutics.

Not long ago, scientists from AstraZeneca analyzed interactions of NAD-binding motifs of approximately 500 NAD-dependent human enzymes towards NAD itself or its analogues and, based on more than 2000 crystal structures, they came to the conclusion that the NAD-binding protein class is largely underrepresented in drug discovery. There are nearly 500 human protein kinases and their inhibitors, which bind at the ATP-binding domain of these enzymes and have been successfully developed and are now on the market. In contrast, only a few drugs interacting with the NAD-binding domain of NAD-dependent enzymes have been approved.

On the other hand, pyridines and niacin-related compounds are also environmentally and dietarily available, often abundantly too, as a consequence of human activities or behaviors, e.g., when pesticides or food additives are used in agriculture or in the food industry. These compounds, exactly like any other pyridine-like drug, may interfere variously with endogenous NAD metabolism of cells, thus, becoming fully accessible and eventually dangerous for human health. Recent accumulating evidence suggests that such environmental toxicity is possible and likely mediated by off-targeting effects on NAD metabolism.

This Special Issue will focus on NAD metabolism and the latest developments and discovery of small-molecule regulators acting within this pathway, i.e., activators or inhibitors, both naturally occurring and synthetic. One focus is on the NAD-dependent enzymes that are linked to selected disorders or diseases and on their drug targeting for therapy. Moreover, outside this, it can also be focused on the environmental pyridines still “orphan” of function or missing their targets. Original research articles, perspectives, and reviews on the discovery, mechanism of action, characterization, validation, comparative analysis, structural investigation, etc., are all welcome.

Prof. Dr. Riccardo Petrelli
Prof. Dr. Giuseppe Orsomando
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • NAD metabolism
  • NAD enzymology
  • NAD biosynthesis
  • NAD degradation
  • pyridine drugs
  • niacin
  • vitamin B3
  • drug discovery
  • NAD-based therapeutics

Published Papers (3 papers)

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Research

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17 pages, 1496 KiB  
Article
5-((3-Amidobenzyl)oxy)nicotinamides as SIRT2 Inhibitors: A Study of Constrained Analogs
by Teng Ai, Daniel J. Wilson and Liqiang Chen
Molecules 2023, 28(22), 7655; https://doi.org/10.3390/molecules28227655 - 18 Nov 2023
Cited by 1 | Viewed by 895
Abstract
SIRT2 is a member of NAD+-dependent sirtuins and its inhibition has been proposed as a promising therapeutic approach for treating human diseases, including neurodegenerative diseases, cancer, and infections. Expanding SIRT2 inhibitors based on the 3-aminobenzyloxy nicotinamide core structure, we have synthesized [...] Read more.
SIRT2 is a member of NAD+-dependent sirtuins and its inhibition has been proposed as a promising therapeutic approach for treating human diseases, including neurodegenerative diseases, cancer, and infections. Expanding SIRT2 inhibitors based on the 3-aminobenzyloxy nicotinamide core structure, we have synthesized and evaluated constrained analogs and selected stereoisomers. Our structure-activity relationship (SAR) study has revealed that 2,3-constrained (S)-isomers possess enhanced in vitro enzymatic inhibitory activity against SIRT2 and retain excellent selectivity over SIRT1 and SIRT3, provided that a suitable ring A is used. This current study further explores SIRT2 inhibitors based on the 3-aminobenzyloxy nicotinamide scaffold and contributes to the discovery of potent, selective SIRT2 inhibitors that have been actively pursued for their potential therapeutic applications. Full article
(This article belongs to the Special Issue NAD Metabolism and Related Drug Compounds)
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19 pages, 9244 KiB  
Article
A Versatile Continuous Fluorometric Enzymatic Assay for Targeting Nicotinate Phosphoribosyltransferase
by Gabriele Minazzato, Elisa Marangoni, Carlo Fortunato, Riccardo Petrelli, Loredana Cappellacci, Fabio Del Bello, Leonardo Sorci, Massimiliano Gasparrini, Francesco Piacente, Santina Bruzzone and Nadia Raffaelli
Molecules 2023, 28(3), 961; https://doi.org/10.3390/molecules28030961 - 18 Jan 2023
Cited by 2 | Viewed by 1832
Abstract
The maintenance of a proper NAD+ pool is essential for cell survival, and tumor cells are particularly sensitive to changes in coenzyme levels. In this view, the inhibition of NAD+ biosynthesis is considered a promising therapeutic approach. Current research is mostly [...] Read more.
The maintenance of a proper NAD+ pool is essential for cell survival, and tumor cells are particularly sensitive to changes in coenzyme levels. In this view, the inhibition of NAD+ biosynthesis is considered a promising therapeutic approach. Current research is mostly focused on targeting the enzymes nicotinamide phosphoribosyltransferase (NAMPT) and nicotinate phosphoribosyltransferase (NAPRT), which regulate NAD+ biosynthesis from nicotinamide and nicotinic acid, respectively. In several types of cancer cells, both enzymes are relevant for NAD+ biosynthesis, with NAPRT being responsible for cell resistance to NAMPT inhibition. While potent NAMPT inhibitors have been developed, only a few weak NAPRT inhibitors have been identified so far, essentially due to the lack of an easy and fast screening assay. Here we present a continuous coupled fluorometric assay whereby the product of the NAPRT-catalyzed reaction is enzymatically converted to NADH, and NADH formation is measured fluorometrically. The assay can be adapted to screen compounds that interfere with NADH excitation and emission wavelengths by coupling NADH formation to the cycling reduction of resazurin to resorufin, which is monitored at longer wavelengths. The assay system was validated by confirming the inhibitory effect of some NA-related compounds on purified human recombinant NAPRT. In particular, 2-hydroxynicotinic acid, 2-amminonicotinic acid, 2-fluoronicotinic acid, pyrazine-2-carboxylic acid, and salicylic acid were confirmed as NAPRT inhibitors, with Ki ranging from 149 to 348 µM. Both 2-hydroxynicotinic acid and pyrazine-2-carboxylic acid were found to sensitize OVCAR-5 cells to the NAMPT inhibitor FK866 by decreasing viability and intracellular NAD+ levels. Full article
(This article belongs to the Special Issue NAD Metabolism and Related Drug Compounds)
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Review

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31 pages, 1201 KiB  
Review
Nicotinamide Riboside, a Promising Vitamin B3 Derivative for Healthy Aging and Longevity: Current Research and Perspectives
by Andrei Biţă, Ion Romulus Scorei, Maria Viorica Ciocîlteu, Oana Elena Nicolaescu, Andreea Silvia Pîrvu, Ludovic Everard Bejenaru, Gabriela Rău, Cornelia Bejenaru, Antonia Radu, Johny Neamţu, George Dan Mogoşanu and Steven A. Benner
Molecules 2023, 28(16), 6078; https://doi.org/10.3390/molecules28166078 - 15 Aug 2023
Cited by 3 | Viewed by 4061
Abstract
Many studies have suggested that the oxidized form of nicotinamide adenine dinucleotide (NAD+) is involved in an extensive spectrum of human pathologies, including neurodegenerative disorders, cardiomyopathy, obesity, and diabetes. Further, healthy aging and longevity appear to be closely related to NAD [...] Read more.
Many studies have suggested that the oxidized form of nicotinamide adenine dinucleotide (NAD+) is involved in an extensive spectrum of human pathologies, including neurodegenerative disorders, cardiomyopathy, obesity, and diabetes. Further, healthy aging and longevity appear to be closely related to NAD+ and its related metabolites, including nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). As a dietary supplement, NR appears to be well tolerated, having better pharmacodynamics and greater potency. Unfortunately, NR is a reactive molecule, often unstable during its manufacturing, transport, and storage. Recently, work related to prebiotic chemistry discovered that NR borate is considerably more stable than NR itself. However, immediately upon consumption, the borate dissociates from the NR borate and is lost in the body through dilution and binding to other species, notably carbohydrates such as fructose and glucose. The NR left behind is expected to behave pharmacologically in ways identical to NR itself. This review provides a comprehensive summary (through Q1 of 2023) of the literature that makes the case for the consumption of NR as a dietary supplement. It then summarizes the challenges of delivering quality NR to consumers using standard synthesis, manufacture, shipping, and storage approaches. It concludes by outlining the advantages of NR borate in these processes. Full article
(This article belongs to the Special Issue NAD Metabolism and Related Drug Compounds)
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