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.

Polypharmacology of epacadostat: a potent and selective inhibitor of the tumor associated carbonic anhydrases IX and XII

2019 ◽  
Vol 55 (40) ◽  
pp. 5720-5723 ◽  
Author(s):  
Andrea Angeli ◽  
Marta Ferraroni ◽  
Alessio Nocentini ◽  
Silvia Selleri ◽  
Paola Gratteri ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Selective Inhibitor ◽  
Carbonic Anhydrase Inhibitor ◽  
Carbonic Anhydrases ◽  
Indoleamine 2,3 Dioxygenase

Epacadostat (EPA), a selective indoleamine-2,3-dioxygenase 1 (IDO1) inhibitor, has been investigatedin vitroas a human (h) Carbonic Anhydrase Inhibitor (CAI).

scholarly journals Polymorphisms in Brucella Carbonic anhydrase II mediate CO2 dependence and fitness in vivo

2019 ◽  
Author(s):  
JM García-Lobo ◽  
Y Ortiz ◽  
C González-Riancho ◽  
A Seoane ◽  
B Arellano-Reynoso ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Primary Cultures ◽  
Low Frequency ◽  
Carbonic Anhydrase Ii ◽  
Carbonic Anhydrases ◽  
Significant Difference ◽  
Dependent Strain

AbstractSome Brucella isolates are known to require an increased concentration of CO2 for growth, especially in the case of primary cultures obtained directly from infected animals. Moreover, the different Brucella species and biovars show a characteristic pattern of CO2 requirement, and this trait has been included among the routine typing tests used for species and biovar differentiation. By comparing the differences in gene content among different CO2-dependent and CO2-independent Brucella strains we have confirmed that carbonic anhydrase II (CA II), is the enzyme responsible for this phenotype in all the Brucella strains tested. Brucella species contain two carbonic anhydrases of the β family, CA I and CA II; genetic polymorphisms exist for both of them in different isolates, but only those putatively affecting the activity of CA II correlate with the CO2 requirement of the corresponding isolate. Analysis of these polymorphisms does not allow the determination of CA I functionality, while the polymorphisms in CA II consist of small deletions that cause a frameshift that changes the C-terminus of the protein, probably affecting its dimerization status, essential for the activity.CO2-independent mutants arise easily in vitro, although with a low frequency ranging from 10−6 to 10−10 depending on the strain. These mutants carry compensatory mutations that produce a full length CA II. At the same time, no change was observed in the sequence coding for CA I. A competitive index assay designed to evaluate the fitness of a CO2-dependent strain compared to its corresponding CO2-independent strain revealed that while there is no significant difference when the bacteria are grown in culture plates, growth in vivo in a mouse model of infection provides a significant advantage to the CO2-dependent strain. This could explain why some Brucella isolates are CO2-dependent in primary isolation. The polymorphism described here also allows the in silico determination of the CO2 requirement status of any Brucella strain.

scholarly journals Identification of inhibitors of SARS-CoV-2 3CL-Pro enzymatic activity using a small molecule in-vitro repurposing screen

2020 ◽  
Author(s):  
Maria Kuzikov ◽  
Elisa Costanzi ◽  
Jeanette Reinshagen ◽  
Francesca Esposito ◽  
Laura Vangeel ◽  
...  
Keyword(s):  
Enzymatic Activity ◽  
Small Molecules ◽  
Drug Target ◽  
Treatment Options ◽  
Cleavage Sites ◽  
X Ray ◽  
Binding Characteristics ◽  
Main Protease ◽  
Ic50 Values

Compound repurposing is an important strategy for the identification of effective treatment options against SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (3CL-Pro), also termed M-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyproteins pp1a and pp1ab at multiple distinct cleavage sites. We here report the results of a repurposing program involving 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and small molecules regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, and have identified 62 additional compounds with IC50 values below 1 uM and profiled their selectivity towards Chymotrypsin and 3CL-Pro from the MERS virus. A subset of 8 inhibitors showed anti-cytopathic effect in a Vero-E6 cell line and the compounds thioguanosine and MG-132 were analysed for their predicted binding characteristics to SARS-CoV-2 3CL-Pro. The X-ray crystal structure of the complex of myricetin and SARS-Cov-2 3CL-Pro was solved at a resolution of 1.77 Angs., showing that myricetin is covalently bound to the catalytic Cys145 and therefore inhibiting its enzymatic activity.

An Original Aspirin-Containing Carbonic Anhydrase 9 Inhibitor Overcomes Hypoxia-induced Drug Resistance to Enhance The Efficacy of Myocardial Protection

2021 ◽  
Author(s):  
Wen Zhou ◽  
Bin Zhang ◽  
Keyu Fan ◽  
Xiaojian Yin ◽  
Jinfeng Liu ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Carbonic Anhydrase ◽  
Myocardial Ischemia ◽  
Ph Value ◽  
Acquired Resistance ◽  
Vital Role ◽  
Carbonic Anhydrase 9 ◽  
Myocardial Hypoxia

Abstract Purpose Hypoxic microenvironment plays a vital role in myocardial ischemia injury, generally leading to the resistance of chemotherapeutic drugs. This induces an intriguing study on mechanism exploration and prodrug design to overcome the hypoxia induced drug resistance.Methods In this study, we hypothesized that the overexpression of carbonic anhydrase 9 (CAIX) in myocardial cells is closely related to the drug resistance. Herein, bioinformatics analysis, gene knockdown and overexpression assay certificated the correlation between CAIX overexpression and hypoxia. An original aspirin-containing CAIX inhibitor AcAs has been developed.Results Based on the downregulation of CAIX level, both in vitro and in vivo, AcAs can overcome the acquired resistance, and more effectively attenuate myocardial ischemia and hypoxia injury than that of aspirin. CAIX inhibitor is believed to recover the extracellular pH value so as to ensure the stable effect of aspirin.Conclusion Results indicate great potential of CAIX inhibitor for further application in myocardial hypoxia injury therapy.

scholarly journals Azobenzene-based inhibitors of human carbonic anhydrase II

2015 ◽  
Vol 11 ◽  
pp. 1129-1135 ◽  
Author(s):  
Leander Simon Runtsch ◽  
David Michael Barber ◽  
Peter Mayer ◽  
Michael Groll ◽  
Dirk Trauner ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Catalytic Activity ◽  
Carbonic Anhydrase ◽  
Drug Class ◽  
Carbonic Anhydrase Ii ◽  
Carbonic Anhydrases ◽  
X Ray ◽  
X Ray Crystallography ◽  
Human Carbonic Anhydrase

Aryl sulfonamides are a widely used drug class for the inhibition of carbonic anhydrases. In the context of our program of photochromic pharmacophores we were interested in the exploration of azobenzene-containing sulfonamides to block the catalytic activity of human carbonic anhydrase II (hCAII). Herein, we report the synthesis and in vitro evaluation of a small library of nine photochromic sulfonamides towards hCAII. All molecules are azobenzene-4-sulfonamides, which are substituted by different functional groups in the 4´-position and were characterized by X-ray crystallography. We aimed to investigate the influence of electron-donating or electron-withdrawing substituents on the inhibitory constant K i. With the aid of an hCAII crystal structure bound to one of the synthesized azobenzenes, we found that the electronic structure does not strongly affect inhibition. Taken together, all compounds are strong blockers of hCAII with K i = 25–65 nM that are potentially photochromic and thus combine studies from chemical synthesis, crystallography and enzyme kinetics.

scholarly journals Practical Islamic and Research Ethics: The Use of Animal Model in Orthopaedic Research

2020 ◽  
Vol 18 (2) ◽  
Author(s):  
Nurul Hafiza Mohd Jan ◽  
Ahmad Hafiz Zulkifly ◽  
Mohd Zulfadzli Ibrahim
Keyword(s):  
Animal Models ◽  
Animal Studies ◽  
Treatment Options ◽  
Practical Application ◽  
Ethical Guidelines ◽  
Islamic Ethics ◽  
Mortality And Morbidity ◽  
Orthopaedic Research ◽  
Animal Use

Introduction: The growing of mortality and morbidity that are related to orthopaedic cases have contributed to the development and innovation of technology which actively seeks for the best treatment options. In order to achieve the goal, animal models have been used as a bridge from in vitro to the clinical study to provide insights both as a precursor and beneficial to human-based research. Many animal models have been developed to investigate bone regeneration, pathological changes and reparation. Besides, animal models are used more commonly in orthopaedic innovation and development. Through the practical application of the 5Rs (reduction, refinement, replacement, reproducibility and responsibility) principles that correlate with the Islamic ethics in this research, this study aimed to provide an ultimate ethical standard on animal use in orthopaedic research. Besides the texts of the Qur’an and the prophetic narrations (hadith), both Muslim jurists (fuqaha) and ethicists’ relevant opinion on these matters would be unveiled. As from the Islamic viewpoints, the usage of animal is permittable for scientific research purposed within the permissible limits described by the  Shari’ah  and guided by ethical values derived from the Divine Revelations (al-wahy al-Ilahyi). By practising the guidelines, it is hoped that these ethical guidelines will help to educate the Muslim scholars and researchers to substantive improvements in terms of quality and the ethical standards of animal studies in orthopaedic research.

scholarly journals Genetic Therapy for Intervertebral Disc Degeneration

2021 ◽  
Vol 22 (4) ◽  
pp. 1579 ◽  
Author(s):  
Eun Roh ◽  
Anjani Darai ◽  
Jae Kyung ◽  
Hyemin Choi ◽  
Su Kwon ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Animal Models ◽  
Intervertebral Disc ◽  
Treatment Options ◽  
Mammalian Target Of Rapamycin ◽  
Chronic Lower Back Pain ◽  
Technological Advances ◽  
Disc Cells ◽  
Ivd Degeneration

Intervertebral disc (IVD) degeneration can cause chronic lower back pain (LBP), leading to disability. Despite significant advances in the treatment of discogenic LBP, the limitations of current treatments have sparked interest in biological approaches, including growth factor and stem cell injection, as new treatment options for patients with chronic LBP due to IVD degeneration (IVDD). Gene therapy represents exciting new possibilities for IVDD treatment, but treatment is still in its infancy. Literature searches were conducted using PubMed and Google Scholar to provide an overview of the principles and current state of gene therapy for IVDD. Gene transfer to degenerated disc cells in vitro and in animal models is reviewed. In addition, this review describes the use of gene silencing by RNA interference (RNAi) and gene editing by the clustered regularly interspaced short palindromic repeats (CRISPR) system, as well as the mammalian target of rapamycin (mTOR) signaling in vitro and in animal models. Significant technological advances in recent years have opened the door to a new generation of intradiscal gene therapy for the treatment of chronic discogenic LBP.

scholarly journals Beta-lactam antibiotics as reserve medications for the treatment of drug-resistant tuberculosis

2021 ◽  
Vol 66 (5-6) ◽  
pp. 78-85
Author(s):  
G. N. Mozhokina ◽  
A. G. Samoilova ◽  
I. A. Vasilyeva
Keyword(s):  
Drug Resistance ◽  
Review Article ◽  
Drug Resistant ◽  
Beta Lactam ◽  
Drug Resistant Tuberculosis ◽  
Beta Lactam Antibiotics ◽  
Resistant Tuberculosis ◽  
Extensive Drug Resistance ◽  
Tuberculosis Activity

The review article presents an analysis of literature data on the necessity to expand the range of medications possessing anti-tuberculosis activity for the treatment of the most severe forms of drug-resistant tuberculosis through the use of beta-lactam antibiotics in chemotherapy regimens. The mechanism of action of beta- lactam antibiotics on mycobacterium tuberculosis is shown, and the results of in vitro studies to assess their anti-tuberculosis activity are presented. Clinical studies on the use of carbapenems prove the feasibility of their use for the treatment of patients with tuberculosis with multiple and extensive drug resistance of the pathogen.

scholarly journals Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens

Genes ◽  
2018 ◽  
Vol 9 (9) ◽  
pp. 461 ◽  
Author(s):  
Ewa Ksiezopolska ◽  
Toni Gabaldón
Keyword(s):  
Drug Resistance ◽  
Fungal Infections ◽  
Current Knowledge ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Developed Countries ◽  
Antifungal Drugs ◽  
Opportunistic Pathogens ◽  
Evolutionary Mechanisms

Fungal infections, such as candidiasis caused by Candida, pose a problem of growing medical concern. In developed countries, the incidence of Candida infections is increasing due to the higher survival of susceptible populations, such as immunocompromised patients or the elderly. Existing treatment options are limited to few antifungal drug families with efficacies that vary depending on the infecting species. In this context, the emergence and spread of resistant Candida isolates are being increasingly reported. Understanding how resistance can evolve within naturally susceptible species is key to developing novel, more effective treatment strategies. However, in contrast to the situation of antibiotic resistance in bacteria, few studies have focused on the evolutionary mechanisms leading to drug resistance in fungal species. In this review, we will survey and discuss current knowledge on the genetic bases of resistance to antifungal drugs in Candida opportunistic pathogens. We will do so from an evolutionary genomics perspective, focusing on the possible evolutionary paths that may lead to the emergence and selection of the resistant phenotype. Finally, we will discuss the potential of future studies enabled by current developments in sequencing technologies, in vitro evolution approaches, and the analysis of serial clinical isolates.

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