Unveiling the effects of berenil, a DNA-binding drug, on Trypanosoma cruzi: implications for kDNA ultrastructure and replication

Zuma, Aline Araújo; Cavalcanti, Danielle Pereira; Zogovich, Marcelo; Machado, Ana Carolina L.; Mendes, Isolda C.; Thiry, Marc; Galina, Antônio; Souza, Wanderley de; Machado, Carlos Renato; Motta, María Cristina M.

doi:10.1007/s00436-014-4199-8

Cited by 23 publications

(20 citation statements)

References 38 publications

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“…In combination therapy, drugs sharing the same mode of action tend to yield a synergistic effect, which can be defined as the greater effect of two drugs in combination than the sum of each drug when acting separately, or an additive effect, in which the effect of two drugs in combination is equal to the sum of each drug when acting separately 10 , 11 . Previous studies reported that both CF and DA have an AT-rich DNA-binding activity on Mycobacterium species and Trypanosoma cruzi , respectively 14 , 15 . AT-rich DNA-binding drugs influence the RNA synthesis and DNA replication by selectively interacting with AT-rich regions in DNA.…”

Section: Introductionmentioning

confidence: 98%

“…Several AT-rich DNA-binding drugs are known to possess anti-bacterial, anti-protozoal and anti-cancer activities 14 – 16 . In apicomplexan parasites, AT-rich regions are commonly found, especially in the mitochondrial and apicoplast genomes, making them an attractive target for AT-rich DNA-binding drugs 15 , 17 . Moreover, toxic side effects of CF and DA were found to be non-overlapping 3 , 7 .…”

Section: Introductionmentioning

confidence: 99%

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Chemotherapeutic efficacies of a clofazimine and diminazene aceturate combination against piroplasm parasites and their AT-rich DNA-binding activity on Babesia bovis

Tuvshintulga

AbouLaila

Sivakumar

et al. 2017

Sci Rep

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Recently, we reported that clofazimine (CF) has an anti-piroplasm activity, but it could not completely eliminate parasites in the host. The currently available anti-piroplasm drug, diminazene aceturate (DA), has sometimes been reported to have toxic side effects. In the present study, we evaluated the combination treatment with CF and DA against piroplasms both in vitro and in vivo. Additionally, mRNA level and DNA amounts were analyzed in CF‒ and DA‒treated Babesia bovis by a qPCR. The CF–DA combination had additive effects on Babesia bovis, B. bigemina, and B. caballi and synergistic effects on Theileria equi. The CF–DA combination chemotherapies against B. microti in mice were more potent than their monotherapies. In the CF‒ and DA‒treated B. bovis, CF dose-dependently down-regulated mRNA level and DNA amounts of extranuclear genes (AT-rich featured), whereas DA down-regulated only DNA amounts of extranuclear genes, but those of nuclear genes were slightly down- or up-regulated by CF and DA. In conclusion, the CF–DA combination has a higher efficiency against piroplasms than CF or DA monotherapies. CF and DA might have an AT-rich DNA-binding activity. All results suggest that the CF–DA combination chemotherapy will be a better choice to treat piroplasmosis instead of DA monotherapy.

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Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Chemotherapeutic efficacies of a clofazimine and diminazene aceturate combination against piroplasm parasites and their AT-rich DNA-binding activity on Babesia bovis

Tuvshintulga

AbouLaila

Sivakumar

et al. 2017

Sci Rep

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“…Drugs may have targets beyond proteins, including DNA and RNA. 91,92 To better model how a compound interacts with all potential targets, we are integrating compound-nucleic acid interaction modeling into CANDO. Finally, we are working with collaborators to validate the predictions from the various pipelines in preclinical and clinical studies, which represents the ultimate test of the CANDO platform.…”

Section: Discussionmentioning

confidence: 99%

Fingerprinting CANDO: Increased Accuracy with Structure and Ligand Based Shotgun Drug Repurposing

Schuler

Samudrala

2019

Preprint

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1We have upgraded our Computational Analysis of Novel Drug Opportunities (CANDO) 2 platform for shotgun drug repurposing to include ligand-based, data fusion, and decision tree 3 pipelines. The first version of CANDO implemented a structure-based pipeline that mod-4 eled interactions between compounds and proteins on a large scale, generating compound-5 proteome interaction signatures used to infer similarity of drug behavior; the new pipelines 6 accomplish this by incorporating molecular fingerprints and the Tanimoto coefficient. We 7 obtain improved benchmarking performance with the new pipelines across all three evalua-8 tion metrics used: average indication accuracy, pairwise accuracy, and coverage. The best 9 performing pipeline achieves an average indication accuracy of 19.0% at the top10 cutoff, 10 compared to 11.7% for v1, and 2.2% for a random control. Our results demonstrate that the 11 CANDO drug recovery accuracy is substantially improved by integrating multiple pipelines, 12 thereby enhancing our ability to generate putative therapeutic repurposing candidates, and 13 increasing drug discovery efficiency. 14 Introduction 15 Drug repurposing 16 Bringing a new drug to the market may costs hundreds of millions of dollars and takes years 17 of work. 1 Drug repurposing is the process of discovering a new use for an existing drug. 2,3 18This process may take advantage of existing data on safety and pharmacokinetic properties 19 from previous trials and clinical use to reduce costs and time associated with traditional drug 20 discovery. Classic examples of drug repurposing include sildenafil (Viagra) and thalidomide, 21 which initially were developed to treat chest pain and morning sickness, but were repurposed 22 to treat erectile dysfunction and erythema nodosum leprosum respectively. 2,4,5 Drugs which 23 have already been repurposed once are being researched for even more novel uses. For exam-24 ple, raloxifene was originally indicated for prevention of osteoporosis and was subsequently 25 approved for risk reduction in the development of breast cancer. 6 More recently, raloxifene 26 has been suggested as a possible treatment for Ebola virus disease 7-9 '. These examples of 27 putative and/or successful drug repurposing underlies the diverse mechanisms through which 28 a single compound may treat a variety of disease types. 10,11 High throughput, target-based, 29 and phenotypic screening of compounds can be used to generate putative candidates for re-30 purposing. 12 For example, potential treatments for Zika virus infection were identified using 31 a phenotypic screen. 13 32 Computational drug discovery and repurposing 33 Finding new drugs or new uses for existing drugs computationally takes advantage of the 34 growing amount of data generated from wet lab experiments accessible on the Internet, 35 increased computational power, and higher fidelity of computational models to reality. Ap-36 proaches to computational drug discovery and repurposing have been classified as structure-37 b...

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“…Most Trypanosomatid parasites have catenated kDNA networks [ 7 , 8 ] and it has been proposed that the transition from a non-catenated structure in free-living relatives to the catenated network may have been an important preadaptation for the success of the parasites [ 9 ], furthermore it has been argued that the disruption of kDNA structure can be used as a potential chemotherapy target ([ 10 ] and reviewed in [ 11 ]), [ 12 ]. However, the formation and maintenance of this network is still a major puzzle in spite of significant advances through numerous biochemical and molecular studies (for a review see [ 13 ]).…”

Section: Introductionmentioning

confidence: 99%

Orientation of DNA Minicircles Balances Density and Topological Complexity in Kinetoplast DNA

et al. 2015

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Kinetoplast DNA (kDNA), a unique mitochondrial structure common to trypanosomatid parasites, contains thousands of DNA minicircles that are densely packed and can be topologically linked into a chain mail-like network. Experimental data indicate that every minicircle in the network is, on average, singly linked to three other minicircles (i.e., has mean valence 3) before replication and to six minicircles in the late stages of replication. The biophysical factors that determine the topology of the network and its changes during the cell cycle remain unknown. Using a mathematical modeling approach, we previously showed that volume confinement alone can drive the formation of the network and that it induces a linear relationship between mean valence and minicircle density. Our modeling also predicted a minicircle valence two orders of magnitude greater than that observed in kDNA. To determine the factors that contribute to this discrepancy we systematically analyzed the relationship between the topological properties of the network (i.e., minicircle density and mean valence) and its biophysical properties such as DNA bending, electrostatic repulsion, and minicircle relative position and orientation. Significantly, our results showed that most of the discrepancy between the theoretical and experimental observations can be accounted for by the orientation of the minicircles with volume exclusion due to electrostatic interactions and DNA bending playing smaller roles. Our results are in agreement with the three dimensional kDNA organization model, initially proposed by Delain and Riou, in which minicircles are oriented almost perpendicular to the horizontal plane of the kDNA disk. We suggest that while minicircle confinement drives the formation of kDNA networks, it is minicircle orientation that regulates the topological complexity of the network.

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Unveiling the effects of berenil, a DNA-binding drug, on Trypanosoma cruzi: implications for kDNA ultrastructure and replication

Cited by 23 publications

References 38 publications

Chemotherapeutic efficacies of a clofazimine and diminazene aceturate combination against piroplasm parasites and their AT-rich DNA-binding activity on Babesia bovis

Chemotherapeutic efficacies of a clofazimine and diminazene aceturate combination against piroplasm parasites and their AT-rich DNA-binding activity on Babesia bovis

Fingerprinting CANDO: Increased Accuracy with Structure and Ligand Based Shotgun Drug Repurposing

Orientation of DNA Minicircles Balances Density and Topological Complexity in Kinetoplast DNA

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