Biochemical profiling of anti-HIV prodrug Elsulfavirine (Elpida ®) and its active form VM1500A against a panel of twelve human carbonic anhydrase isoforms

Published on Dec 1, 2021in Journal of Enzyme Inhibition and Medicinal Chemistry4.673
· DOI :10.1080/14756366.2021.1927007
Claudiu T. Supuran152
Estimated H-index: 152
(UniFI: University of Florence),
Alessio Nocentini26
Estimated H-index: 26
(UniFI: University of Florence)
+ 3 AuthorsMikhail Krasavin24
Estimated H-index: 24
(SPbU: Saint Petersburg State University)
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Abstract
The non-nucleoside reverse transcriptase inhibitor VM1500A is approved for the treatment of HIV/AIDS in its N-acyl sulphonamide prodrug form elsulfavirine (Elpida®). Biochemical profiling against twelve human carbonic anhydrase (CA, EC 4.2.1.1) isoforms showed that while elsulfavirine was a weak inhibitor of all isoforms, VM1500A potently and selectively inhibited human (h) hCA VII isoform, a proven target for the therapy of neuropathic pain. The latter is a common neurologic complication of HIV infection and we hypothesise that by using Elpida® in patients may help alleviate this debilitating symptom.
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References47
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#1Alessio Nocentini (UniFI: University of Florence)H-Index: 26
#2Andrea Angeli (UniFI: University of Florence)H-Index: 23
Last. Claudiu T. Supuran (UniFI: University of Florence)H-Index: 152
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Inorganic anions inhibit the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) generally by coordinating to the active site metal ion. Cyanate was reported as a non-coordinating CA inhibitor but those erroneous results were subsequently corrected by another group. We review the anion CA inhibitors (CAIs) in the more general context of drug design studies and the discovery of a large number of inhibitor classes and inhibition mechanisms, including zinc binders (sulphonamides and isosteres, dithio...
18 CitationsSource
#1Andrea Angeli (UniFI: University of Florence)H-Index: 23
#2Fabrizio Carta (UniFI: University of Florence)H-Index: 52
Last. Claudiu T. Supuran (UniFI: University of Florence)H-Index: 152
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#1Claudiu T. Supuran (UniFI: University of Florence)H-Index: 152
Carbonic anhydrase (CA, EC 4.2.1.1) isoforms IX and XII are overexpressed in many hypoxic tumors as a consequence of the hypoxia inducible factor (HIF) activation cascade, being present in limited amounts in normal tissues. These enzymes together with many others are involved in the pH regulation and metabolism of hypoxic cancer cells, and were validated as antitumor targets recently. A multitude of targeting strategies against these enzymes have been proposed and are reviewed in this article. T...
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#1Ercan Soydan (OMU: Ondokuz Mayıs University)H-Index: 5
#2Ahmet Can Olcay (OMU: Ondokuz Mayıs University)H-Index: 1
Last. Claudiu T. Supuran (UniFI: University of Florence)H-Index: 152
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Carbonic anhydrase (CA, EC 4.2.1.1) plays crucial physiological roles in many different organisms, such as in pH regulation, ion transport, and metabolic processes. CA was isolated from the Europea...
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#1Doretta Cuffaro (UniPi: University of Pisa)H-Index: 5
#2Elisa Nuti (UniPi: University of Pisa)H-Index: 25
Last. Armando Rossello (UniPi: University of Pisa)H-Index: 28
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Carbonic anhydrases (CAs) are metalloenzymes responsible for the reversible hydration of carbon dioxide to bicarbonate, a fundamental reaction involved in various physiological and pathological pro...
3 CitationsSource
#1Paolo Guglielmi (Sapienza University of Rome)H-Index: 14
#2Giulia Rotondi (Sapienza University of Rome)H-Index: 3
Last. Claudiu T. Supuran (UniFI: University of Florence)H-Index: 152
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A large library of saccharin and acesulfame derivatives has been synthesised and evaluated against four isoforms of human carbonic anhydrase, the two off-targets hCA I/II and the tumour related iso...
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Coumarins constitute a relatively new class of inhibitors of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), possessing a unique inhibition mechanism, acting as “prodrug inhibitors.” They unde...
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#1Chandra Bhushan Mishra (Sookmyung Women's University)H-Index: 15
#2Manisha Tiwari (DU: University of Delhi)H-Index: 23
Last. Claudiu T. Supuran (UniFI: University of Florence)H-Index: 152
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Carbonic anhydrases (CAs, EC 4.2.1.1) are widely distributed metalloenzymes in both prokaryotes and eukaryotes. They efficiently catalyze the reversible hydration of carbon dioxide to bicarbonate and H+ ions and play a crucial role in regulating many physiological processes. CAs are well-studied drug target for various disorders such as glaucoma, epilepsy, sleep apnea, and high altitude sickness. In the past decades, a large category of diverse families of CA inhibitors (CAIs) have been develope...
35 CitationsSource
#1Alessandro Bonardi (UniFI: University of Florence)H-Index: 10
#2Alessio Nocentini (UniFI: University of Florence)H-Index: 26
Last. Claudiu T. Supuran (UniFI: University of Florence)H-Index: 152
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The “tail-approach” has become a milestone in human carbonic anhydrase inhibitor (hCAI) design for various therapeutics, including antiglaucoma agents. Beside the classical hydrophobic/hydrophilic ...
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#1Patrizio Blandina (UniFI: University of Florence)H-Index: 36
#2Gustavo Provensi (UniFI: University of Florence)H-Index: 17
Last. Claudiu T. Supuran (UniFI: University of Florence)H-Index: 152
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: Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes which use CO2 as substrate, catalysing its interconversion to bicarbonate and a proton. In humans 15 CAs are expressed, 12 of which are catalytically active: the cytosolic CA I-III, VII, XIII, the membrane-bound CA IV, the mitochondrial CA VA and VB, the secreted CA VI, and the transmembrane CA IX, XII, XIV. Nine isoforms are present in the mammalian brain. Evidence supporting that CA inhibitors impair memory in humans has come from stud...
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