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Crystalline Arthritis
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
Preventing extracellular ATP hydrolysis is an additional mechanism to reduce extracellular PPi. Researchers from Tel Aviv Medical Center and University investigated ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (eNPP1), the major ecto-pyrophosphatase in chondrocytes and cartilage-derived matrix vesicles. As a proof of concept, their proprietary nucleotide analogue and eNPP1 inhibitor, SK4, reduced ATP hydrolysis ex vivo in human chondrocytes. Pyrophosphatase inhibition will have to be fine-tuned since a significant reduction in PPi may promote basic calcium phosphate (BCP) deposition in joints and other tissues, such as blood vessels, by altering the inorganic phosphate/PPi ratio.65 Lowering intraarticular PPi should prevent further crystallization but may not affect already-formed CPP deposits.
Phosphonic Acids And Phosphonates As Antimetabolites
Published in Richard L. Hilderbrand, The Role of Phosphonates in Living Systems, 2018
These results have several complications, the most obvious being a fundamental difference in the nature of pyrophosphatases from various sources. As such, the species (1) to (3) have the potential of serving as useful probes for details of enzyme function. Also, one may see here the potential importance of a binding capability associated with the atom, oxygen in the natural system, directly bound to the phosphorus. It is of great significance that this binding capability may be accommodated, at least in some systems, by a functionality attached to that atom rather than by an electron pair directly on the atom. Utilization of this situation is noted later for other systems (Section IV).
The Ultrastructure And Pathobiology Of Urinary Bladder Cancer
Published in George T. Bryan, Samuel M. Cohen, The Pathology of Bladder Cancer, 2017
Bendicht U. Pauli, Joseph Alroy, Ronald S Weinstein
There are differences in normal urinary bladder structure and function between species. The contribution of AUM-plaques to the lumenal membrane of the superficial cells in mammalian urinary bladder is species dependent.55 Intermediate cells in mammalian bladder show considerable species variability. Rat intermediate cells contain fusiform vesicles and appear to be partially differentiated replacements for the superficial cell layer.76,135 In the mouse136 and several other species,72,137 distinctive large whorls of paired membranes are found in intermediate cells, but not in the basal or superficial cell layers. These are not present in dog, cat, common seal, or grey seal.72 The whorls have no thiamine pyrophosphatase activity, but have moderate inosine diphosphatase activity. Central granules of the membrane whorls are acid phosphatase positive.72 Based upon morphological considerations and enzyme activities, it has been suggested that these whorls may represent a form of endoplasmic reticulum.72 This interpretation does not answer the question of their function in an epithelium not known to secrete proteins. Amphibian urinary bladder is considered to be the phylogenic and functional analog of the collecting tubule of the mammalian kidney90,91 and is therefore not considered further in this review.
Small-molecule CD73 inhibitors for the immunotherapy of cancer: a patent and literature review (2017–present)
Published in Expert Opinion on Therapeutic Patents, 2021
Alessio Nocentini, Clemente Capasso, Claudiu T. Supuran
The field of CD73 inhibitors, in the more general context of ectonucleotidase inhibitors, has been reviewed earlier [22,23]. This earlier review considered ectonucleoside triphosphate diphosphohydrolases (NTPDases), ectonucleotide pyrophosphatase/phosphodiesterases (E-NPPs), alkaline phosphatases (APs) and e5NT, as well as applications of inhibitors of these enzymes published in the period 2011–2016, in various therapeutic areas [23]. In this article, we will review the new inhibitors developed in the period from 2016 onwards, focusing our presentation on the antitumor applications of CD73 inhibitors. Although some MAbs will also be mentioned, the main focus of the review will be on the small-molecule inhibitors reported in the scientific and patent literature during the mentioned period.
A study of Rose Bengal against a 2-keto-3-deoxy-d -manno-octulosonate cytidylyltransferase as an antibiotic candidate
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Suwon Kim, Seri Jo, Mi-Sun Kim, Dong Hae Shin
The screening of about two hundred chemical compounds (Supplementary Table 1) was performed with a malachite green assay method which is a photometric method31. The principle of this method is: when KdsBs transfer the cytidine 5′-monophosphate (CMP) moiety from cytidine 5′-triphosphate (CTP) to KDO, CMP-KDO, and pyrophosphate (PPi) are produced. PPi was decomposed into two phosphates by inorganic pyrophosphatase (IPP) and phosphates were measured by the malachite green method. CTP and KDO purchased from Sigma (St. Louis, MO) were used as a real substrate. A colour reagent of the malachite green method for phosphate detection was a mixture of ammonium molybdate ((NH4)6Mo7O24), malachite green solution and Tween 20 in the ratio 1:3:0.1. The mixture was filtered through a 0.20 μm PVDF syringe filter (Younginfrontier Inc., Seoul, Republic of Korea) and allowed to stand at room temperature (RT) for 1 h before use. The probability of inhibitory function of each chemical was investigated by detecting the difference in absorbance between the reaction mixtures with and without KdsBs.
Fully human anti-CD39 antibody potently inhibits ATPase activity in cancer cells via uncompetitive allosteric mechanism
Published in mAbs, 2020
Bradley N. Spatola, Alana G. Lerner, Clifford Wong, Tracy dela Cruz, Megan Welch, Wanchi Fung, Maria Kovalenko, Karolina Losenkova, Gennady G. Yegutkin, Courtney Beers, John Corbin, Vanessa B. Soros
An inhibitor of CD39 should be exquisitely specific, lacking reactivity to other ecto-nucleoside triphosphate diphosphohydrolase (NTPDase) family members that regulate ATP.21 For example, NTPDase2 (CD39L1) activates platelets in the vasculature,21 and NTPDase8 is the major ectonucleotidase active in the liver.22 A disruption of either nucleotide hydrolase’s activity function by a promiscuous NTPDase inhibitor may cause undesired toxicities. Outside of the enzymes of NTPDase family, extracellular nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) and tissue-nonspecific alkaline phosphatase (TNAP) also hydrolyze ATP. However, both enzymes have reduced catalytic activity at neutral pH and are not expected to significantly contribute to ATP catabolism in the slightly acidic TME.2 The published small molecule inhibitors of CD39, such as sodium polyoxotungstate (POM-1), 6-N, N-diethyl-D-β,γ-dibromomethylene-ATP-trisodium salt (ARL-67156), adenylyl-imidophosphate (AMP-PNP), and sodium azide, are neither CD39-specific nor have favorable drug-like properties.23–29 A monoclonal antibody (mAb) inhibitor of CD39 ATPase activity would be anticipated to meet the specificity requirements for a therapeutic.