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

2020 ◽  
Vol 21 (5) ◽  
pp. 1842 ◽  
Author(s):  
Andrea Angeli ◽  
Mariana Pinteala ◽  
Stelian S. Maier ◽  
Bogdan C. Simionescu ◽  
Akram A. Da’dara ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Schistosoma Mansoni ◽  
Drug Target ◽  
Hydration Reaction ◽  
High Catalytic Activity ◽  
Intestinal Schistosomiasis ◽  
Host Parasite ◽  
Inhibition Studies ◽  
Platyhelminth Parasite ◽  
Aromatic Heterocyclic

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 CO2 hydration reaction, similar to that of human CA isoform II with a kcat of 1.2 × 106 s−1 and a kcat/KM of 1.3 × 108 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 (KI values of 737.2 nM−9.25 μM), whereas some heterocyclic compounds inhibited the enzyme with KI values in the range of 124−325 nM. The α-CA from S. mansoni, SmCA, is proposed as a new anti-schistosomiasis drug target.

scholarly journals Anion Inhibition Studies of the β-Class Carbonic Anhydrase CAS3 from the Filamentous Ascomycete Sordaria macrospora

Metabolites ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 93
Author(s):  
Daniela Vullo ◽  
Ronny Lehneck ◽  
William A. Donald ◽  
Stefanie Pöggeler ◽  
Claudiu T. Supuran
Keyword(s):  
Catalytic Activity ◽  
Carbonic Anhydrase ◽  
Small Molecules ◽  
Small Molecule ◽  
Hydration Reaction ◽  
High Catalytic Activity ◽  
Sordaria Macrospora ◽  
Filamentous Ascomycete ◽  
Diethyl Dithiocarbamate ◽  
Inhibition Studies

CAS3 is a newly cloned cytosolic β-class carbonic anhydrase (CA, EC 4.2.1.1) from the filamentous ascomycete Sordaria macrospora. This enzyme has a high catalytic activity for the physiological CO2 hydration reaction and herein, we report the inhibition profile of CAS3 with anions and small molecules. The most effective CAS3 anions/small molecule inhibitors were diethyl-dithiocarbamate, sulfamide, sulfamate, phenyl boronic and phenyl arsonic acids, with KIs in the range of 0.89 mM–97 µM. Anions such as iodide, the pseudohalides, bicarbonate, carbonate, nitrate, nitrite, hydrogensulfide, stannate, selenate, tellurate, tetraborate, perrhenate, perruthenate, selenocyanide and trithiocarbonate were low millimolar CAS3 inhibitors. The light halides, sulfate, hydrogensulfite, peroxydisulfate, diphosphate, divanadate, perchlorate, tetrafluoroborate, fluorosulfonate and iminodisulfonate did not significantly inhibit this enzyme. These data may be useful for developing antifungals based on CA inhibition, considering the fact that many of the inhibitors reported here may be used as lead molecules and, by incorporating the appropriate organic scaffolds, potent nanomolar inhibitors could be developed.

scholarly journals Sulfonamide Inhibition Studies of a New β-Carbonic Anhydrase from the Pathogenic Protozoan Entamoeba histolytica

2018 ◽  
Vol 19 (12) ◽  
pp. 3946 ◽  
Author(s):  
Silvia Bua ◽  
Susanna Haapanen ◽  
Marianne Kuuslahti ◽  
Seppo Parkkila ◽  
Claudiu Supuran
Keyword(s):  
Catalytic Activity ◽  
Carbonic Anhydrase ◽  
Entamoeba Histolytica ◽  
Mechanisms Of Action ◽  
Hydration Reaction ◽  
Lead Compounds ◽  
Inhibition Studies ◽  
Pathogenic Protozoan

A newly described β-carbonic anhydrase (CA, EC 4.2.1.1) from the pathogenic protozoan Entamoeba histolytica, EhiCA, was recently shown to possess a significant catalytic activity for the physiologic CO2 hydration reaction (kcat of 6.7 × 105 s−1 and a kcat/Km of 8.9 × 107 M−1 s−1). A panel of sulphonamides and one sulfamate, some of which are clinically used drugs, were investigated for their inhibitory properties against EhiCA. The best inhibitors detected in the study were 4-hydroxymethyl/ethyl-benzenesulfonamide (KIs of 36–89 nM), whereas some sulfanilyl-sulfonamides showed activities in the range of 285–331 nM. Acetazolamide, methazolamide, ethoxzolamide, and dichlorophenamide were less effective inhibitors (KIs of 509–845 nM) compared to other sulfonamides investigated here. As β-CAs are not present in vertebrates, the present study may be useful for detecting lead compounds for the design of more effective inhibitors with potential to develop anti-infectives with alternative mechanisms of action.

scholarly journals Cloning, Characterization and Anion Inhibition Studies of a β-Carbonic Anhydrase from the Pathogenic Protozoan Entamoeba histolytica

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3112 ◽  
Author(s):  
Susanna Haapanen ◽  
Silvia Bua ◽  
Marianne Kuuslahti ◽  
Seppo Parkkila ◽  
Claudiu Supuran
Keyword(s):  
Catalytic Activity ◽  
Carbonic Anhydrase ◽  
Entamoeba Histolytica ◽  
Enzyme Inhibitors ◽  
Phenylboronic Acid ◽  
Sulfamic Acid ◽  
Hydration Reaction ◽  
High Catalytic Activity ◽  
Lead Compounds ◽  
Pathogenic Protozoan

We report the cloning and catalytic activity of a β-carbonic anhydrase (CA, EC 4.2.1.1), isolated from the pathogenic protozoan Entamoeba histolytica, EhiCA. This enzyme has a high catalytic activity for the physiologic CO2 hydration reaction, with a kcat of 6.7 × 105 s−1 and a kcat/Km of 8.9 × 107 M−1 × s−1. An anion inhibition study of EhiCA with inorganic/organic anions and small molecules revealed that fluoride, chloride, cyanide, azide, pyrodiphosphate, perchlorate, tetrafluoroborate and sulfamic acid did not inhibit the enzyme activity, whereas pseudohalides (cyanate and thiocyanate), bicarbonate, nitrate, nitrite, diethyldithiocarbamate, and many complex inorganic anions showed inhibition in the millimolar range (KIs of 0.51–8.4 mM). The best EhiCA inhibitors were fluorosulfonate, sulfamide, phenylboronic acid and phenylarsonic acid (KIs in the range of 28–86 μM). Since β-CAs are not present in vertebrates, the present study may be useful for detecting lead compounds for the design of effective enzyme inhibitors, with potential to develop anti-infectives with alternative mechanisms of action.

Are Carbonic Anhydrases Suitable Targets to Fight Protozoan Parasitic Diseases?

2019 ◽  
Vol 25 (39) ◽  
pp. 5266-5278 ◽  
Author(s):  
Katia D'Ambrosio ◽  
Claudiu T. Supuran ◽  
Giuseppina De Simone
Keyword(s):  
Drug Resistance ◽  
Animal Models ◽  
Carbonic Anhydrase ◽  
Drug Target ◽  
Treatment Options ◽  
Parasitic Diseases ◽  
Carbonic Anhydrases ◽  
Extensive Drug Resistance ◽  
Protozoan Infections

Protozoans belonging to Plasmodium, Leishmania and Trypanosoma genera provoke widespread parasitic diseases with few treatment options and many of the clinically used drugs experiencing an extensive drug resistance phenomenon. In the last several years, the metalloenzyme Carbonic Anhydrase (CA, EC 4.2.1.1) was cloned and characterized in the genome of these protozoa, with the aim to search for a new drug target for fighting malaria, leishmaniasis and Chagas disease. P. falciparum encodes for a CA (PfCA) belonging to a novel genetic family, the η-CA class, L. donovani chagasi for a β-CA (LdcCA), whereas T. cruzi genome contains an α-CA (TcCA). These three enzymes were characterized in detail and a number of in vitro potent and selective inhibitors belonging to the sulfonamide, thiol, dithiocarbamate and hydroxamate classes were discovered. Some of these inhibitors were also effective in cell cultures and animal models of protozoan infections, making them of considerable interest for the development of new antiprotozoan drugs with a novel mechanism of action.

Coumaronochromone as antibacterial and carbonic anhydrase inhibitors from Aerva persica (Burm.f.) Merr.: experimental and first-principles approaches

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Muhammad Imran ◽  
Ahmad Irfan ◽  
Mohammed A. Assiri ◽  
Sajjad H. Sumrra ◽  
Muhammad Saleem ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
First Principles ◽  
Molecular Electrostatic Potential ◽  
Chemical Constituents ◽  
Bacterial Strains ◽  
Hirshfeld Analysis ◽  
Carbonic Anhydrase Inhibition ◽  
Inhibition Studies ◽  
Lowest Unoccupied Molecular Orbitals

AbstractThe Aerva plants are exceptionally rich in phytochemicals and possess therapeutics potential. Phytochemical screening shows that Aerva persica (Burm.f.) Merr. contains highest contents i.e., total phenolics, flavonoids, flavonols, tannins, alkaloids, carbohydrates, anthraquinones and glycosides. In-vitro antibacterial and enzymatic (carbonic anhydrase) inhibition studies on methanol extracts of A. persica indicated the presence of biological active constituents within chloroform soluble portions. Investigation in the pure constituents on the chloroform portions of A. persica accomplished by column chromatography, NMR and MS analysis. The bioguided isolation yields four chemical constituents of coumaronochromone family, namely aervin (1-4). These pure chemical entities (1-4) showed significant antibacterial activity in the range of 60.05–79.21 µg/ml against various bacterial strains using ampicillin and ciprofloxacin as standard drugs. The compounds 1-4 showed promising carbonic anhydrase inhibition with IC50 values of 19.01, 18.24, 18.65 and 12.92 µM, respectively, using standard inhibitor acetazolamide. First-principles calculations revealed comprehensive intramolecular charge transfer in the studied compounds 1-4. The spatial distribution of highest occupied and lowest unoccupied molecular orbitals, ionization potential, molecular electrostatic potential and Hirshfeld analysis revealed that these coumaronochromone compounds would be proficient biological active compounds. These pure constituents may be used as a new pharmacophore to treat leaukomia, epilepsy, glaucoma and cystic fibrosis.

scholarly journals Spatial expression pattern of serine proteases in the blood fluke Schistosoma mansoni determined by fluorescence RNA in situ hybridization

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Lenka Ulrychová ◽  
Pavel Ostašov ◽  
Marta Chanová ◽  
Michael Mareš ◽  
Martin Horn ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
Schistosoma Mansoni ◽  
Rna Sequencing ◽  
Serine Proteases ◽  
Expression Patterns ◽  
High Sensitivity ◽  
Host Parasite Interactions ◽  
Highly Sensitive ◽  
Host Parasite

Abstract Background The blood flukes of genus Schistosoma are the causative agent of schistosomiasis, a parasitic disease that infects more than 200 million people worldwide. Proteases of schistosomes are involved in critical steps of host–parasite interactions and are promising therapeutic targets. We recently identified and characterized a group of S1 family Schistosoma mansoni serine proteases, including SmSP1 to SmSP5. Expression levels of some SmSPs in S. mansoni are low, and by standard genome sequencing technologies they are marginally detectable at the method threshold levels. Here, we report their spatial gene expression patterns in adult S. mansoni by the high-sensitivity localization assay. Methodology Highly sensitive fluorescence in situ RNA hybridization (FISH) was modified and used for the localization of mRNAs encoding individual SmSP proteases (including low-expressed SmSPs) in tissues of adult worms. High sensitivity was obtained due to specifically prepared tissue and probes in combination with the employment of a signal amplification approach. The assay method was validated by detecting the expression patterns of a set of relevant reference genes including SmCB1, SmPOP, SmTSP-2, and Sm29 with localization formerly determined by other techniques. Results FISH analysis revealed interesting expression patterns of SmSPs distributed in multiple tissues of S. mansoni adults. The expression patterns of individual SmSPs were distinct but in part overlapping and were consistent with existing transcriptome sequencing data. The exception were genes with significantly low expression, which were also localized in tissues where they had not previously been detected by RNA sequencing methods. In general, SmSPs were found in various tissues including reproductive organs, parenchymal cells, esophagus, and the tegumental surface. Conclusions The FISH-based assay provided spatial information about the expression of five SmSPs in adult S. mansoni females and males. This highly sensitive method allowed visualization of low-abundantly expressed genes that are below the detection limits of standard in situ hybridization or by RNA sequencing. Thus, this technical approach turned out to be suitable for sensitive localization studies and may also be applicable for other trematodes. The results suggest that SmSPs may play roles in diverse processes of the parasite. Certain SmSPs expressed at the surface may be involved in host–parasite interactions. Graphic abstract

scholarly journals Anion inhibition studies of the Zn(II)-bound ι-carbonic anhydrase from the Gram-negative bacterium Burkholderia territorii

2021 ◽  
Vol 36 (1) ◽  
pp. 372-376
Author(s):  
Andrea Petreni ◽  
Viviana De Luca ◽  
Andrea Scaloni ◽  
Alessio Nocentini ◽  
Clemente Capasso ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Negative Bacterium ◽  
Gram Negative ◽  
Inhibition Studies

scholarly journals Synthesis and Human Carbonic Anhydrase I, II, IX, and XII Inhibition Studies of Sulphonamides Incorporating Mono-, Bi- and Tricyclic Imide Moieties

2021 ◽  
Vol 14 (7) ◽  
pp. 693
Author(s):  
Kalyan K. Sethi ◽  
KM Abha Mishra ◽  
Saurabh M. Verma ◽  
Daniela Vullo ◽  
Fabrizio Carta ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Carbonic Anhydrase ◽  
Docking Studies ◽  
Carbonic Anhydrases ◽  
Molecular Docking Studies ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Carbonic Anhydrase I ◽  
Human Carbonic Anhydrase ◽  
Inhibition Studies

New derivatives were synthesised by reaction of amino-containing aromatic sulphonamides with mono-, bi-, and tricyclic anhydrides. These sulphonamides were investigated as human carbonic anhydrases (hCAs, EC 4.2.1.1) I, II, IX, and XII inhibitors. hCA I was inhibited with inhibition constants (Kis) ranging from 49 to >10,000 nM. The physiologically dominant hCA II was significantly inhibited by most of the sulphonamide with the Kis ranging between 2.4 and 4515 nM. hCA IX and hCA XII were inhibited by these sulphonamides in the range of 9.7 to 7766 nM and 14 to 316 nM, respectively. The structure–activity relationships (SAR) are rationalised with the help of molecular docking studies.

Susceptibilities of Various Snail Intermediate Hosts of Schistosoma mansoni to Different Strains of the Parasite

1965 ◽  
Vol 39 (4) ◽  
pp. 363-376 ◽  
Author(s):  
M.F.A. Saoud
Keyword(s):  
Puerto Rico ◽  
Schistosoma Mansoni ◽  
Intermediate Hosts ◽  
Considerable Evidence ◽  
The Past ◽  
Host Parasite Relationship ◽  
Parasite Relationship ◽  
Different Strains ◽  
Host Parasite ◽  
Comprehensive Studies

In the past two decades, considerable evidence has accumulated in the literature about the differences in the susceptibility of various intermediate hosts of Schistosoma mansoni to different strains of the parasite. Comprehensive studies on this aspect of host-parasite relationship have been published by Files & Cram (1949), Abdel-Malek (1950) and Files (1951). The results of more recent studies have been reported by Wright (1962) and Saoud (1964).In the present paper, the writer has studied the susceptibility of four intermediate hosts of S. mansoni from Brazil, Puerto Rico, Egypt and Tanganyika to some strains of the parasite.

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