ENPP1, an Old Enzyme with New Functions, and Small Molecule Inhibitors—A STING in the Tale of ENPP1

Onyedibe, Kenneth I.; Wang, Wanhe; Sintim, Herman O.

doi:10.3390/molecules24224192

Cited by 77 publications

(78 citation statements)

References 94 publications

(156 reference statements)

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“…However, the high acidity of nucleotide-based ENPP1 inhibitors dampens its oral bioavailability. Off-target biological effects of those drugs would be magnified, because their structure resembles that of natural substrates [120]. These drawbacks of newly-developed ENPP1 inhibitors shed light on CDNs delivery systems using nanocarriers to improve drug efficacy.…”

Section: Nanocarriersmentioning

confidence: 99%

cGAS-STING pathway in cancer biotherapy

et al. 2020

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The activation of the cGAS-STING pathway has tremendous potential to improve anti-tumor immunity by generating type I interferons. In recent decades, we have witnessed that producing dsDNA upon various stimuli is an initiative factor, triggering the cGAS-SING pathway for a defensive host. The understanding of both intracellular cascade reaction and the changes of molecular components gains insight into type I IFNs and adaptive immunity. Based on the immunological study, the STING-cGAS pathway is coupled to cancer biotherapy. The most challenging problem is the limited therapeutic effect. Therefore, people view 5, 6-dimethylxanthenone-4-acetic acid, cyclic dinucleotides and various derivative as cGAS-STING pathway agonists. Even so, these agonists have flaws in decreasing biotherapeutic efficacy. Subsequently, we exploited agonist delivery systems (nanocarriers, microparticles and hydrogels). The article will discuss the activation of the cGAS-STING pathway and underlying mechanisms, with an introduction of cGAS-STING agonists, related clinical trials and agonist delivery systems.

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Section: Nanocarriersmentioning

confidence: 99%

cGAS-STING pathway in cancer biotherapy

et al. 2020

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“…At the extracellular level, adenosine comes from the dephosphorylation of ATP and AMP via the membrane clusters CD39 and CD73, respectively. Aside of CD39, pyrophosphatases (ENPP1/3) is expressed in many tissues including macrophages and can degrade ATP to AMP leading to enhance adenosine production [9].…”

Section: Source and Mechanism Of Action Of Adenosinementioning

confidence: 99%

Adenosine and the Cardiovascular System: The Good and the Bad

Guieu

Deharo

Maille

et al. 2020

JCM

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Adenosine is a nucleoside that impacts the cardiovascular system via the activation of its membrane receptors, named A1R, A2AR, A2BR and A3R. Adenosine is released during hypoxia, ischemia, beta-adrenergic stimulation or inflammation and impacts heart rhythm and produces strong vasodilation in the systemic, coronary or pulmonary vascular system. This review summarizes the main role of adenosine on the cardiovascular system in several diseases and conditions. Adenosine release participates directly in the pathophysiology of atrial fibrillation and neurohumoral syncope. Adenosine has a key role in the adaptive response in pulmonary hypertension and heart failure, with the most relevant effects being slowing of heart rhythm, coronary vasodilation and decreasing blood pressure. In other conditions, such as altitude or apnea-induced hypoxia, obstructive sleep apnea, or systemic hypertension, the adenosinergic system activation appears in a context of an adaptive response. Due to its short half-life, adenosine allows very rapid adaptation of the cardiovascular system. Finally, the effects of adenosine on the cardiovascular system are sometimes beneficial and other times harmful. Future research should aim to develop modulating agents of adenosine receptors to slow down or conversely amplify the adenosinergic response according to the occurrence of different pathologic conditions.

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“…The hydrolysis of 2′-3′-cGAMP messenger by the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP1) constitutes one of these mechanisms ( 58 ). Since its discovery, this extracellular enzyme has aroused great interest because of its strong therapeutic potential ( 59 ) as inhibitors of ENPP1 could help potentiate cGAS-STING signaling ( 60 ). cGAS-STING pathway is also modulated by the epidermal growth factor receptor (EGFR) ( 61 ).…”

Section: Origin and Evolution Of The Molecular Mechanisms Of The Nuclmentioning

confidence: 99%

Cyclic Guanosine Monophosphate–Adenosine Monophosphate Synthase (cGAS), a Multifaceted Platform of Intracellular DNA Sensing

Verrier

Langevin

2021

Front. Immunol.

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Innate immune pathways are the first line of cellular defense against pathogen infections ranging from bacteria to Metazoa. These pathways are activated following the recognition of pathogen associated molecular patterns (PAMPs) by membrane and cytosolic pattern recognition receptors. In addition, some of these cellular sensors can also recognize endogenous danger-associated molecular patterns (DAMPs) arising from damaged or dying cells and triggering innate immune responses. Among the cytosolic nucleic acid sensors, the cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) synthase (cGAS) plays an essential role in the activation of the type I interferon (IFNs) response and the production of pro-inflammatory cytokines. Indeed, upon nucleic acid binding, cGAS synthesizes cGAMP, a second messenger mediating the activation of the STING signaling pathway. The functional conservation of the cGAS-STING pathway during evolution highlights its importance in host cellular surveillance against pathogen infections. Apart from their functions in immunity, cGAS and STING also play major roles in nuclear functions and tumor development. Therefore, cGAS-STING is now considered as an attractive target to identify novel biomarkers and design therapeutics for auto-inflammatory and autoimmune disorders as well as infectious diseases and cancer. Here, we review the current knowledge about the structure of cGAS and the evolution from bacteria to Metazoa and present its main functions in defense against pathogens and cancer, in connection with STING. The advantages and limitations of in vivo models relevant for studying the cGAS-STING pathway will be discussed for the notion of species specificity and in the context of their integration into therapeutic screening assays targeting cGAG and/or STING.

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ENPP1, an Old Enzyme with New Functions, and Small Molecule Inhibitors—A STING in the Tale of ENPP1

Cited by 77 publications

References 94 publications

cGAS-STING pathway in cancer biotherapy

cGAS-STING pathway in cancer biotherapy

Adenosine and the Cardiovascular System: The Good and the Bad

Cyclic Guanosine Monophosphate–Adenosine Monophosphate Synthase (cGAS), a Multifaceted Platform of Intracellular DNA Sensing

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