Carbonic anhydrase inhibitors and their potential in a range of therapeutic areas

Supuran, Claudiu T.

doi:10.1080/13543776.2018.1523897

Cited by 141 publications

(146 citation statements)

References 73 publications

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“…In humans there are 15 CA isoforms, [9] many of which are relevant drug targets involved in several pathologies. [10][11][12][13][14] To date, several CA inhibitors are routinely administered in the treatment of glaucoma, epilepsy, or as diuretics, [15,16] with some of them in clinical development as antitumor agents, [17,18] In order to detect CA2 by NMR, the protein was directly expressed and labelled in the cytosol of human cells (see the Experimental Methods section of the Supporting Information). [19,20] NMR signals arising from [ 15 N]-CA2 were clearly detected in the 1 H-15 N correlation spectra (Supporting Information, Figure S1), indicating that the intracellular protein is soluble and free from interactions with slow-tumbling cellular components, which would otherwise increase transverse relaxation and cause signal broadening beyond detection.…”

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confidence: 99%

Drug Screening in Human Cells by NMR Spectroscopy Allows the Early Assessment of Drug Potency

et al. 2020

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Structure‐based drug development is often hampered by the lack of in vivo activity of promising compounds screened in vitro, due to low membrane permeability or poor intracellular binding selectivity. Herein, we show that ligand screening can be performed in living human cells by “intracellular protein‐observed” NMR spectroscopy, without requiring enzymatic activity measurements or other cellular assays. Quantitative binding information is obtained by fast, inexpensive 1H NMR experiments, providing intracellular dose‐ and time‐dependent ligand binding curves, from which kinetic and thermodynamic parameters linked to cell permeability and binding affinity and selectivity are obtained. The approach was applied to carbonic anhydrase and, in principle, can be extended to any NMR‐observable intracellular target. The results obtained are directly related to the potency of candidate drugs, that is, the required dose. The application of this approach at an early stage of the drug design pipeline could greatly increase the low success rate of modern drug development.

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Drug Screening in Human Cells by NMR Spectroscopy Allows the Early Assessment of Drug Potency

et al. 2020

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“…Sulfonamides are the main class of zinc-binding CA inhibitors (CAIs), [2,3] but several other classes of inhibitors have also been reported recently, such as the thiols, dithiocarbamates, coumarins, polyamines and selenols among others [30,31]. We have thus included a range of sulfonamides in an initial screening program to find the compounds targeting this new protozoan enzyme.…”

Section: Enzyme K Cat (Smentioning

confidence: 99%

“…We have thus included a range of sulfonamides in an initial screening program to find the compounds targeting this new protozoan enzyme. Sulfonamides, thiols, dithiocarbamates and selenols possess a similar mechanism of action, as they bind to the zinc ion within the active site cavity and substitute the non-protein zinc ligand (the hydroxide ion/water molecule) [2,3,30,31]. Here, we investigated a panel of 24 sulfonamides (compounds 1−24, whose molecular structure is depicted in Figure 1) for their ability to inhibit recombinant SmCA (rSmCA).…”

Section: Enzyme K Cat (Smentioning

confidence: 99%

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Sulfonamide Inhibition Studies of an α-Carbonic Anhydrase from Schistosoma mansoni, a Platyhelminth Parasite Responsible for Schistosomiasis

Angeli

Pinteală²,

Maier³

et al. 2020

IJMS

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Schistosomiasis is a debilitating infection provoked by parasitic flatworms called schistosomes. The species Schistosoma mansoni is endemic in Africa, where it causes intestinal schistosomiasis. Recently, an α-carbonic anhydrase (CA, EC 4.2.1.1) was cloned and characterized from this organism and designated as SmCA. The protein is expressed in the tegument (skin) of S. mansoni at the host-parasite interface. Recombinant SmCA possesses high catalytic activity in the CO 2 hydration reaction, similar to that of human CA isoform II with a k cat of 1.2 × 10 6 s −1 and a k cat /K M of 1.3 × 10 8 M −1 ·s −1 . It has been found that schistosomes whose SmCA gene is suppressed using RNA interference are unable to establish a robust infection in mice, suggesting that the chemicals that inhibit SmCA function should have the same debilitating effect on the parasites. In this study, a collection of aromatic/heterocyclic sulfonamides were investigated as possible SmCA inhibitors. Several sulfonamides inhibited SmCA with medium to weak potency (K I values of 737.2 nM−9.25 µM), whereas some heterocyclic compounds inhibited the enzyme with K I values in the range of 124−325 nM. The α-CA from S. mansoni, SmCA, is proposed as a new anti-schistosomiasis drug target.

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“…It has a relatively low solubility in water, but it reacts with this solvent (at the neutral pH) to produce bicarbonate anion and protons. These two ions play a crucial role in maintaining pH homeostasis in living systems and their equilibration with CO 2 is controlled by the activity of the enzymes Carbonic Anhydrase (CA, EC 4.2.1.1) [1][2][3][4][5] . CAs are extremely efficient catalysts, and they are widespread in organisms all over the phylogenetic tree.…”

Section: Introductionmentioning

confidence: 99%

A structure-based approach towards the identification of novel antichagasic compounds: Trypanosoma cruzi carbonic anhydrase inhibitors

Llanos

Sbaraglini

Villalba

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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Trypanosoma cruzi carbonic anhydrase (TcCA) has recently emerged as an interesting target for the design of new compounds to treat Chagas disease. In this study we report the results of a structure-based virtual screening campaign to identify novel and selective TcCA inhibitors. The combination of properly validated computational methodologies such as comparative modelling, molecular dynamics and docking simulations allowed us to find high potency hits, with KI values in the nanomolar range. The compounds also showed trypanocidal effects against T. cruzi epimastigotes and trypomastigotes. All the candidates are selective for inhibiting TcCA over the human isoform CA II, which is encouraging in terms of possible therapeutic safety and efficacy.

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Carbonic anhydrase inhibitors and their potential in a range of therapeutic areas

Cited by 141 publications

References 73 publications

Drug Screening in Human Cells by NMR Spectroscopy Allows the Early Assessment of Drug Potency

Drug Screening in Human Cells by NMR Spectroscopy Allows the Early Assessment of Drug Potency

Sulfonamide Inhibition Studies of an α-Carbonic Anhydrase from Schistosoma mansoni, a Platyhelminth Parasite Responsible for Schistosomiasis

A structure-based approach towards the identification of novel antichagasic compounds: Trypanosoma cruzi carbonic anhydrase inhibitors

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