Carbonic Anhydrases as Drug Targets: General Presentation

2009 ◽  
pp. 13-38 ◽  
Author(s):  
Claudiu T. Supuran
Keyword(s):  
Drug Targets ◽  
Carbonic Anhydrases

scholarly journals Aryl-4,5-dihydro-1H-pyrazole-1-carboxamide Derivatives Bearing a Sulfonamide Moiety Show Single-digit Nanomolar-to-Subnanomolar Inhibition Constants against the Tumor-associated Human Carbonic Anhydrases IX and XII

2020 ◽  
Vol 21 (7) ◽  
pp. 2621
Author(s):  
Priya Hargunani ◽  
Nikhil Tadge ◽  
Mariangela Ceruso ◽  
Janis Leitans ◽  
Andris Kazaks ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Inhibitory Activity ◽  
Phenyl Ring ◽  
Drug Targets ◽  
Binding Mode ◽  
Docking Studies ◽  
Carbonic Anhydrases ◽  
Single Digit ◽  
Ca Ix ◽  
Shed Light

A series of new 3-phenyl-5-aryl-N-(4-sulfamoylphenyl)-4,5-dihydro-1H-pyrazole-1-carboxamide derivatives was designed here, synthesized, and studied for carbonic anhydrase (CAs, EC 4.2.1.1) inhibitory activity against the human (h) isozymes I, II, and VII (cytosolic, off-target isoforms), and IX and XII (anticancer drug targets). Generally, CA I was not effectively inhibited, whereas effective inhibitors were identified against both CAs II (KIs in the range of 5.2–233 nM) and VII (KIs in the range of 2.3–350 nM). Nonetheless, CAs IX and XII were the most susceptible isoforms to this class of inhibitors. In particular, compounds bearing an unsubstituted phenyl ring at the pyrazoline 3 position showed 1.3–1.5 nM KIs against CA IX. In contrast, a subset of derivatives having a 4-halo-phenyl at the same position of the aromatic scaffold even reached subnanomolar KIs against CA XII (0.62–0.99 nM). Docking studies with CA IX and XII were used to shed light on the derivative binding mode driving the preferential inhibition of the tumor-associated CAs. The identified potent and selective CA IX/XII inhibitors are of interest as leads for the development of new anticancer strategies.

Carbonic anhydrases from Trypanosoma and Leishmania as anti-protozoan drug targets

2017 ◽  
Vol 25 (5) ◽  
pp. 1543-1555 ◽  
Author(s):  
Alane B. Vermelho ◽  
Giseli R. Capaci ◽  
Igor A. Rodrigues ◽  
Verônica S. Cardoso ◽  
Ana Maria Mazotto ◽  
...  
Keyword(s):  
Drug Targets ◽  
Carbonic Anhydrases

The α and β Classes Carbonic Anhydrases from Helicobacter pylori as Novel Drug Targets

2008 ◽  
Vol 14 (7) ◽  
pp. 622-630 ◽  
Author(s):  
Hiroaki Takeuchi ◽  
Claudiu Supuran ◽  
Saburo Onishi ◽  
Isao Nishimori
Keyword(s):  
Helicobacter Pylori ◽  
Drug Targets ◽  
Carbonic Anhydrases ◽  
Novel Drug ◽  
Novel Drug Targets

scholarly journals Transport Metabolons and Acid/Base Balance in Tumor Cells

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 899 ◽  
Author(s):  
Holger M. Becker ◽  
Joachim W. Deitmer
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Drug Targets ◽  
Ph Regulation ◽  
Host Cells ◽  
Bicarbonate Transport ◽  
Carbonic Anhydrases ◽  
Acid Base Balance ◽  
Acid Base ◽  
Base Balance

Solid tumors are metabolically highly active tissues, which produce large amounts of acid. The acid/base balance in tumor cells is regulated by the concerted interplay between a variety of membrane transporters and carbonic anhydrases (CAs), which cooperate to produce an alkaline intracellular, and an acidic extracellular, environment, in which cancer cells can outcompete their adjacent host cells. Many acid/base transporters form a structural and functional complex with CAs, coined “transport metabolon”. Transport metabolons with bicarbonate transporters require the binding of CA to the transporter and CA enzymatic activity. In cancer cells, these bicarbonate transport metabolons have been attributed a role in pH regulation and cell migration. Another type of transport metabolon is formed between CAs and monocarboxylate transporters, which mediate proton-coupled lactate transport across the cell membrane. In this complex, CAs function as “proton antenna” for the transporter, which mediate the rapid exchange of protons between the transporter and the surroundings. These transport metabolons do not require CA catalytic activity, and support the rapid efflux of lactate and protons from hypoxic cancer cells to allow sustained glycolytic activity and cell proliferation. Due to their prominent role in tumor acid/base regulation and metabolism, transport metabolons might be promising drug targets for new approaches in cancer therapy.

Bacterial, fungal and protozoan carbonic anhydrases as drug targets

2015 ◽  
Vol 19 (12) ◽  
pp. 1689-1704 ◽  
Author(s):  
Clemente Capasso ◽  
Claudiu T Supuran
Keyword(s):  
Drug Targets ◽  
Carbonic Anhydrases

scholarly journals Multivalent Carbonic Anhydrases Inhibitors

2019 ◽  
Vol 20 (21) ◽  
pp. 5352 ◽  
Author(s):  
Fabrizio Carta ◽  
Pascal Dumy ◽  
Claudiu T. Supuran ◽  
Jean-Yves Winum
Keyword(s):  
Anticancer Agents ◽  
Drug Targets ◽  
Diagnostic Tools ◽  
Biomolecular Recognition ◽  
Carbonic Anhydrases ◽  
Biological Targets ◽  
Processing Enzymes ◽  
Zinc Metalloenzymes ◽  
Antiglaucoma Agents ◽  
Isoform Selectivity

Biomolecular recognition using a multivalent strategy has been successfully applied, this last decade on several biological targets, especially carbohydrate-processing enzymes, proteases, and phosphorylases. This strategy is based on the fact that multivalent interactions of several inhibitory binding units grafted on a presentation platform may enhance the binding affinity and selectivity. The zinc metalloenzymes carbonic anhydrases (CAs, EC 4.2.1.1) are considered as drug targets for several pathologies, and different inhibitors found clinical applications as diuretics, antiglaucoma agents, anticonvulsants, and anticancer agents/diagnostic tools. Their main drawback is related to the lack of isoform selectivity leading to serious side effects for all pathologies in which they are employed. Thus, the multivalent approach may open new opportunities in the drug design of innovative isoform-selective carbonic anhydrase inhibitors with biomedical applications.

scholarly journals A Highlight on the Inhibition of Fungal Carbonic Anhydrases as Drug Targets for the Antifungal Armamentarium

2021 ◽  
Vol 22 (9) ◽  
pp. 4324
Author(s):  
Claudiu T. Supuran ◽  
Clemente Capasso
Keyword(s):  
Drug Targets ◽  
Fungal Growth ◽  
Pathogenic Fungi ◽  
Fungal Spore ◽  
Antifungal Drugs ◽  
Dependent Manner ◽  
Carbonic Anhydrases ◽  
Living Organisms ◽  
Opportunistic Pathogenic

Carbon dioxide (CO2), a vital molecule of the carbon cycle, is a critical component in living organisms’ metabolism, performing functions that lead to the building of compounds fundamental for the life cycle. In all living organisms, the CO2/bicarbonate (HCO3−) balancing is governed by a superfamily of enzymes, known as carbonic anhydrases (CAs, EC 4.2.1.1). CAs catalyze the pivotal physiological reaction, consisting of the reversible hydration of the CO2 to HCO3− and protons. Opportunistic and pathogenic fungi can sense the environmental CO2 levels, which influence their virulence or environmental subsistence traits. The fungal CO2-sensing is directly stimulated by HCO3− produced in a CA-dependent manner, which directly activates adenylyl cyclase (AC) involved in the fungal spore formation. The interference with CA activity may impair fungal growth and virulence, making this approach interesting for designing antifungal drugs with a novel mechanism of action: the inhibition of CAs linked to the CO2/HCO3−/pH chemosensing and signaling. This review reports that sulfonamides and their bioisosteres as well as inorganic anions can inhibit in vitro the β- and α-CAs from the fungi, suggesting how CAs may be considered as a novel “pathogen protein” target of many opportunistic, pathogenic fungi.

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