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

Llanos, Manuel A.; Sbaraglini, María Laura; Villalba, María Luisa; Ruiz, María Daniela; Carrillo, Carolina; Soto, Catalina Dirney Alba; Talevi, Alan; Angeli, Andrea; Parkkila, Seppo; Gavernet, Luciana

doi:10.1080/14756366.2019.1677638

Cited by 17 publications

(11 citation statements)

References 78 publications

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“…Therefore, a biological effect is not often observed in the other stages of the insect's development [43]. Finally, the authors suggest that CRISPR-Cas9 may be a promising tool for [21] with the MicroED technique applied by Clabbers et al [39]. For illustrative purposes, the human carbonic anhydrase (hCA) image was used; however, the idea of the scheme is this application for studying TcCA with the inhibitors selected by the workflow proposed by Llanos et al [21].…”

Section: Carbonic α-Anhydrase and The Inhibitors Sulfonamides Thiolsmentioning

confidence: 99%

“…In recent years, factors that have hindered the development of new drugs have been extensively discussed in the literature. The lack of accurate biomarkers for treatment, failure in diagnoses, diversity of strains of the parasite, problems with the standardization of methodologies such as in vivo animal models, different host cell culture lines and problems in the translation process among other factors are barriers for the development of new drugs [ 6 , 13 , 20 , 21 ].…”

Section: Drugs Targets and Inhibitorsmentioning

confidence: 99%

“…This assumption was supported by a few in vitro studies that demonstrated the ability of thiols and hydroxamates to inhibit the three phases of the pathogen’s life cycle [ 31 ]. Based on these studies, TcCA is emerging as a new and promising therapeutic target [ 21 ]. Llanos et al used a structure-based approach to identify new compounds that inhibit T. cruzi carbonic anhydrase (TcCA) where 10 compounds from 255 were selected for testing against TcCA [ 21 ].…”

Section: Drugs Targets and Inhibitorsmentioning

confidence: 99%

“…Based on these studies, TcCA is emerging as a new and promising therapeutic target [ 21 ]. Llanos et al used a structure-based approach to identify new compounds that inhibit T. cruzi carbonic anhydrase (TcCA) where 10 compounds from 255 were selected for testing against TcCA [ 21 ]. The authors attested that the combination of computational methodologies allowed the finding of high potency compounds with KI values in the nanomolar range and were selective to inhibit TcCA (which have trypanocidal effects against T. cruzi epimastigotes and trypomastigotes).…”

Section: Drugs Targets and Inhibitorsmentioning

confidence: 99%

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Chagas Disease: Perspectives on the Past and Present and Challenges in Drug Discovery

et al. 2020

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Chagas disease still has no effective treatment option for all of its phases despite being discovered more than 100 years ago. The development of commercial drugs has been stagnating since the 1960s, a fact that sheds light on the question of how drug discovery research has progressed and taken advantage of technological advances. Could it be that technological advances have not yet been sufficient to resolve this issue or is there a lack of protocol, validation and standardization of the data generated by different research teams? This work presents an overview of commercial drugs and those that have been evaluated in studies and clinical trials so far. A brief review is made of recent target-based and phenotypic studies based on the search for molecules with anti-Trypanosoma cruzi action. It also discusses how proteochemometric (PCM) modeling and microcrystal electron diffraction (MicroED) can help in the case of the lack of a 3D protein structure; more specifically, Trypanosoma cruzi carbonic anhydrase.

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Section: Carbonic α-Anhydrase and The Inhibitors Sulfonamides Thiolsmentioning

confidence: 99%

Section: Drugs Targets and Inhibitorsmentioning

confidence: 99%

Section: Drugs Targets and Inhibitorsmentioning

confidence: 99%

Section: Drugs Targets and Inhibitorsmentioning

confidence: 99%

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Chagas Disease: Perspectives on the Past and Present and Challenges in Drug Discovery

et al. 2020

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“…In recent years, CAs have been investigated in detail in pathogens such as bacteria and protozoa [13][14][15][16]. One aim of such work is the search for new antibiotics and anti-infectives that exhibit novel mechanisms of action [17][18][19][20]. In this context, schistosomiasis, a tropical disease caused by trematode parasites of the genus Schistosoma, has been neglected.…”

Section: Introductionmentioning

confidence: 99%

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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The carbonic anhydrase enzymes as new targets for the management of neglected tropical diseases

Renzi,

Ladu,

Carta

et al. 2024

Archiv der Pharmazie

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Diseases caused by protozoan parasites represent a huge challenge to global health care, due to the lack of selective and efficient treatments for the management and spreading of such complex pathologies. The protozoans Trypanosoma cruzi (T. cruzi) and Leishmania spp. are the etiological agents of the so‐called neglected tropical diseases (NTDs), that is, Chagas disease (CD) and leishmaniasis, respectively. In such a context, the metalloenzymes carbonic anhydrases (CAs; EC 4.2.1.1) emerged as potential protozoan druggable enzymes, being involved in the parasites’ life cycle. Several studies suggested the relevance of the protozoan‐expressed CAs as future candidates for the management of NTDs.

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

Cited by 17 publications

References 78 publications

Chagas Disease: Perspectives on the Past and Present and Challenges in Drug Discovery

Chagas Disease: Perspectives on the Past and Present and Challenges in Drug Discovery

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

The carbonic anhydrase enzymes as new targets for the management of neglected tropical diseases

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