Emerging role of carbonic anhydrase inhibitors

2021 ◽  
Vol 135 (10) ◽  
pp. 1233-1249
Author(s):  
Claudiu T. Supuran
Keyword(s):  
Carbonic Anhydrase ◽  
Pathogenic Bacteria ◽  
Acute Mountain Sickness ◽  
Proof Of Concept ◽  
Mountain Sickness ◽  
Antiobesity Agents ◽  
New Applications ◽  
Human Isoforms

Abstract Inhibition of carbonic anhydrase (CA, EC 4.2.1.1) was clinically exploited for decades, as most modern diuretics were obtained considering as lead molecule acetazolamide, the prototypical CA inhibitor (CAI). The discovery and characterization of multiple human CA (hCA) isoforms, 15 of which being known today, led to new applications of their inhibitors. They include widely clinically used antiglaucoma, antiepileptic and antiobesity agents, antitumor drugs in clinical development, as well as drugs for the management of acute mountain sickness and idiopathic intracranial hypertension (IIH). Emerging roles of several CA isoforms in areas not generally connected to these enzymes were recently documented, such as in neuropathic pain, cerebral ischemia, rheumatoid arthritis, oxidative stress and Alzheimer’s disease. Proof-of-concept studies thus emerged by using isoform-selective inhibitors, which may lead to new clinical applications in such areas. Relevant preclinical models are available for these pathologies due to the availability of isoform-selective CAIs for all human isoforms, belonging to novel classes of compounds, such as coumarins, sulfocoumarins, dithiocarbamates, benzoxaboroles, apart the classical sulfonamide inhibitors. The inhibition of CAs from pathogenic bacteria, fungi, protozoans or nematodes started recently to be considered for obtaining anti-infectives with a new mechanism of action.

scholarly journals The Effect of Nanoparticles on the Structure and Enzymatic Activity of Human Carbonic Anhydrase I and II

Molecules ◽  
2020 ◽  
Vol 25 (19) ◽  
pp. 4405
Author(s):  
Celia Cabaleiro-Lago ◽  
Martin Lundqvist
Keyword(s):  
Carbonic Anhydrase ◽  
Conformational Changes ◽  
Catalytic Efficiency ◽  
The Body ◽  
Carbonic Anhydrases ◽  
Nanoparticle Surface ◽  
Mountain Sickness ◽  
Obesity And Cancer ◽  
Final Effect ◽  
Human Isoforms

Human carbonic anhydrases (hCAs) belong to a well characterized group of metalloenzymes that catalyze the conversion of carbonic dioxide into bicarbonate. There are currently 15 known human isoforms of carbonic anhydrase with different functions and distribution in the body. This links to the relevance of hCA variants to several diseases such as glaucoma, epilepsy, mountain sickness, ulcers, osteoporosis, obesity and cancer. This review will focus on two of the human isoforms, hCA I and hCA II. Both are cytosolic enzymes with similar topology and 60% sequence homology but different catalytic efficiency and stability. Proteins in general adsorb on surfaces and this is also the case for hCA I and hCA II. The adsorption process can lead to alteration of the original function of the protein. However, if the function is preserved interesting biotechnological applications can be developed. This review will cover the knowledge about the interaction between hCAs and nanomaterials. We will highlight how the interaction may lead to conformational changes that render the enzyme inactive. Moreover, the importance of different factors on the final effect on hCAs, such as protein stability, protein hydrophobic or charged patches and chemistry of the nanoparticle surface will be discussed.

scholarly journals Characterization of the Opp Peptide Transporter ofCorynebacterium pseudotuberculosisand Its Role in Virulence and Pathogenicity

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Pablo M. R. O. Moraes ◽  
Nubia Seyffert ◽  
Wanderson M. Silva ◽  
Thiago L. P. Castro ◽  
Renata F. Silva ◽  
...  
Keyword(s):  
Pathogenic Bacteria ◽  
Etiologic Agent ◽  
Peptide Transporter ◽  
Intercellular Signaling ◽  
Wild Type ◽  
Cell Nutrition ◽  
Oligopeptide Permease ◽  
Extracellular Environment

Despite the economic importance of caseous lymphadenitis (CLA), a chronic disease caused byCorynebacterium pseudotuberculosis, few genes related to the virulence of its etiologic agent have been characterized. The oligopeptide permease (Opp) transporters are located in the plasma membrane and have functions generally related to the uptake of peptides from the extracellular environment. These peptide transporters, in addition to having an important role in cell nutrition, also participate in the regulation of various processes involving intercellular signaling, including the control of the expression of virulence genes in pathogenic bacteria. To study the role of Opp inC. pseudotuberculosis, an OppD deficient strain was constructed via simple crossover with a nonreplicative plasmid carrying part of theoppDgene sequence. As occurred to the wild-type, the ΔoppDstrain showed impaired growth when exposed to the toxic glutathione peptide (GSH), indicating two possible scenarios: (i) that this component can be internalized by the bacterium through an Opp-independent pathway or (ii) that there is toxicity while the peptide is extracellular. Additionally, the ΔoppDmutant presented a reduced ability to adhere to and infect macrophages compared to the wild-type, although both strains exhibit the same potential to colonize spleens and cause injury and death to infected mice.

Intracranial Pressure at High Altitude and Acute Mountain Sickness

1995 ◽  
Vol 89 (2) ◽  
pp. 201-204 ◽  
Author(s):  
A. D. Wright ◽  
C. H. E. Imray ◽  
M. S. C. Morrissey ◽  
R. J. Marchbanks ◽  
A. R. Bradwell
Keyword(s):  
Intracranial Pressure ◽  
High Altitude ◽  
Acute Hypoxia ◽  
Acute Mountain Sickness ◽  
Raised Intracranial Pressure ◽  
Rapid Ascent ◽  
Mountain Sickness ◽  
Pressure Changes ◽  
Serial Measurements

1. Raised intracranial pressure has been noted in severe forms of acute mountain sickness and high-altitude cerebral oedema, but the role of intracranial pressure in the pathogenesis of mild to moderate acute mountain sickness is unknown. 2. Serial measurements of intracranial pressure were made indirectly by assessing changes in tympanic membrane displacement in 24 healthy subjects on rapid ascent to 5200 m. 3. Acute hypoxia at 3440 m was associated with a rise in intracranial pressure, but no difference was found in pressure changes at 4120 or 5200 m in subjects with or without symptoms of acute mountain sickness. 4. Raised intracranial pressure, though temporarily associated with acute hypoxia, is not a feature of acute mountain sickness with mild or moderate symptoms.

Adhesion of Selected Bifidobacterium Strains to Human Intestinal Mucus and the Role of Adhesion in Enteropathogen Exclusion

2005 ◽  
Vol 68 (12) ◽  
pp. 2672-2678 ◽  
Author(s):  
M. CARMEN COLLADO ◽  
MIGUEL GUEIMONDE ◽  
MANUEL HERNÁNDEZ ◽  
YOLANDA SANZ ◽  
SEPPO SALMINEN
Keyword(s):  
Bacterial Adhesion ◽  
Pathogenic Bacteria ◽  
Animal Origin ◽  
Enterobacter Sakazakii ◽  
Intestinal Mucus ◽  
Probiotic Strains ◽  
Strain Dependent ◽  
Better Than

The ability of potential probiotic strains to adhere to the intestinal mucosa and exclude and displace pathogens is of utmost importance for therapeutic manipulation of the enteric microbiota. The ability of seven selected human bifidobacterial strains and five human enteropathogenic strains to adhere to human intestinal mucus was analyzed and compared with that of four strains isolated from chicken intestines. The adhesion of the bifidobacterial strains ranged from 3 to 16% depending on the strain. Bifidobacterium strains of animal origin adhered significantly better than did strains of human origin. Of the pathogenic bacteria, Escherichia coli NCTC 8603 had the highest adhesion value (20%), Salmonella Typhimurium ATCC 29631, Enterobacter sakazakii ATCC 29544, and Clostridium difficile ATCC 9689 had adhesion values ranging from 10 to 15%, and Listeria monocytogenes ATCC 15313 had the lowest adhesive value (3%). The ability of these bifidobacteria to inhibit pathogen adhesion and to displace pathogens previously adhering to mucus was also tested. The inhibition of pathogens adhesion by these bifidobacterial strains was variable and clearly strain dependent. In general, bifidobacterial strains of animal origin were better able to inhibit and displace pathogens than were human strains. Preliminary characterization of bacterial adhesion was accomplished using different pretreatments to explore adhesion mechanisms. The results indicate that different molecules are implicated in the adhesion of bifidobacteria to the human intestinal mucus, constituting a multifactorial process.

scholarly journals Characterization of the Erwinia chrysanthemi gan Locus, Involved in Galactan Catabolism

2007 ◽  
Vol 189 (19) ◽  
pp. 7053-7061 ◽  
Author(s):  
Aurélie Delangle ◽  
Anne-France Prouvost ◽  
Virginie Cogez ◽  
Jean-Pierre Bohin ◽  
Jean-Marie Lacroix ◽  
...  
Keyword(s):  
Abc Transporter ◽  
Transport System ◽  
Pathogenic Bacteria ◽  
Erwinia Chrysanthemi ◽  
Potato Tubers ◽  
Inner Membrane ◽  
Saintpaulia Ionantha ◽  
Genes Encoding

ABSTRACT β-1,4-Galactan is a major component of the ramified regions of pectin. Analysis of the genome of the plant pathogenic bacteria Erwinia chrysanthemi revealed the presence of a cluster of eight genes encoding proteins potentially involved in galactan utilization. The predicted transport system would comprise a specific porin GanL and an ABC transporter made of four proteins, GanFGK2. Degradation of galactans would be catalyzed by the periplasmic 1,4-β-endogalactanase GanA, which released oligogalactans from trimer to hexamer. After their transport through the inner membrane, oligogalactans would be degraded into galactose by the cytoplasmic 1,4-β-exogalactanase GanB. Mutants affected for the porin or endogalactanase were unable to grow on galactans, but they grew on galactose and on a mixture of galactotriose, galactotetraose, galactopentaose, and galactohexaose. Mutants affected for the periplasmic galactan binding protein, the transporter ATPase, or the exogalactanase were only able to grow on galactose. Thus, the phenotypes of these mutants confirmed the functionality of the gan locus in transport and catabolism of galactans. These mutations did not affect the virulence of E. chrysanthemi on chicory leaves, potato tubers, or Saintpaulia ionantha, suggesting an accessory role of galactan utilization in the bacterial pathogeny.

scholarly journals A unique peptide deformylase platform to rationally design and challenge novel active compounds

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Sonia Fieulaine ◽  
Rodolphe Alves de Sousa ◽  
Laure Maigre ◽  
Karim Hamiche ◽  
Mickael Alimi ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
Peptide Deformylase ◽  
Binding Modes ◽  
Proof Of Concept ◽  
Compound Structure ◽  
3 Dimensional ◽  
Design And Synthesis ◽  
Relationship Analysis

Abstract Peptide deformylase (PDF) is considered an excellent target to develop antibiotics. We have performed an extensive characterization of a new PDF from the pathogen Streptococcus agalactiae, showing properties similar to other known PDFs. S. agalactiae PDF could be used as PDF prototype as it allowed to get complete sets of 3-dimensional, biophysical and kinetic data with virtually any inhibitor compound. Structure-activity relationship analysis with this single reference system allowed us to reveal distinct binding modes for different PDF inhibitors and the key role of a hydrogen bond in potentiating the interaction between ligand and target. We propose this protein as an irreplaceable tool, allowing easy and relevant fine comparisons between series, to design, challenge and validate novel series of inhibitors. As proof-of-concept, we report here the design and synthesis of effective specific bacterial PDF inhibitors of an oxadiazole series with potent antimicrobial activity against a multidrug resistant clinical isolate.

Mechanisms of action of acetazolamide in the prophylaxis and treatment of acute mountain sickness

2007 ◽  
Vol 102 (4) ◽  
pp. 1313-1322 ◽  
Author(s):  
David E. Leaf ◽  
David S. Goldfarb
Keyword(s):  
Metabolic Acidosis ◽  
Carbonic Anhydrase ◽  
Sleep Quality ◽  
Carotid Body ◽  
Acute Mountain Sickness ◽  
Respiratory Acidosis ◽  
Respiratory Alkalosis ◽  
Mechanisms Of Action ◽  
Systemic Effects ◽  
Mountain Sickness

Acetazolamide, a potent carbonic anhydrase (CA) inhibitor, is the most commonly used and best-studied agent for the amelioration of acute mountain sickness (AMS). The actual mechanisms by which acetazolamide reduces symptoms of AMS, however, remain unclear. Traditionally, acetazolamide's efficacy has been attributed to inhibition of CA in the kidneys, resulting in bicarbonaturia and metabolic acidosis. The result is offsetting hyperventilation-induced respiratory alkalosis and allowance of chemoreceptors to respond more fully to hypoxic stimuli at altitude. Studies performed on both animals and humans, however, have shown that this explanation is unsatisfactory and that the efficacy of acetazolamide in the context of AMS is likely due to a multitude of effects. This review summarizes the known systemic effects of acetazolamide and incorporates them into a model encompassing several factors that are likely to play a key role in the drug's efficacy. Such factors include not only metabolic acidosis resulting from renal CA inhibition but also improvements in ventilation from tissue respiratory acidosis, improvements in sleep quality from carotid body CA inhibition, and effects of diuresis.

P6.20 ROLE OF ALTERED VASCULAR REACTIVITY IN THE PATHOPHYSIOLOGY OF ACUTE MOUNTAIN SICKNESS

2015 ◽  
Vol 12 (C) ◽  
pp. 29 ◽  
Author(s):  
Rosa Maria Bruno* ◽  
Guido Giardini ◽  
Sandro Malacrida ◽  
Bruna Catuzzo ◽  
Sabina Armenia ◽  
...  
Keyword(s):  
Vascular Reactivity ◽  
Acute Mountain Sickness ◽  
Mountain Sickness

Autonomic cardiovascular regulation in subjects with acute mountain sickness

2005 ◽  
Vol 289 (6) ◽  
pp. H2364-H2372 ◽  
Author(s):  
Paola A. Lanfranchi ◽  
Roberto Colombo ◽  
George Cremona ◽  
Paolo Baderna ◽  
Liliana Spagnolatti ◽  
...  
Keyword(s):  
High Altitude ◽  
Potential Role ◽  
Acute Mountain Sickness ◽  
Low Frequency ◽  
Short Term ◽  
Mountain Sickness ◽  
Low Altitude ◽  
Normalized Units ◽  
Hypoxic Gas Mixture

The aims of this study were 1) to evaluate whether subjects suffering from acute mountain sickness (AMS) during exposure to high altitude have signs of autonomic dysfunction and 2) to verify whether autonomic variables at low altitude may identify subjects who are prone to develop AMS. Forty-one mountaineers were studied at 4,559-m altitude. AMS was diagnosed using the Lake Louise score, and autonomic cardiovascular function was explored using spectral analysis of R-R interval and blood pressure (BP) variability on 10-min resting recordings. Seventeen subjects (41%) had AMS. Subjects with AMS were older than those without AMS ( P < 0.01). At high altitude, the low-frequency (LF) component of systolic BP variability (LFSBP) was higher ( P = 0.02) and the LF component of R-R variability in normalized units (LFRRNU) was lower ( P = 0.001) in subjects with AMS. After 3 mo, 21 subjects (43% with AMS) repeated the evaluation at low altitude at rest and in response to a hypoxic gas mixture. LFRRNU was similar in the two groups at baseline and during hypoxia at low altitude but increased only in subjects without AMS at high altitude ( P < 0.001) and did not change between low and high altitude in subjects with AMS. Conversely, LFSBP increased significantly during short-term hypoxia only in subjects with AMS, who also had higher resting BP ( P < 0.05) than those without AMS. Autonomic cardiovascular dysfunction accompanies AMS. Marked LFSBP response to short-term hypoxia identifies AMS-prone subjects, supporting the potential role of an exaggerated individual chemoreflex vasoconstrictive response to hypoxia in the genesis of AMS.

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