Computer-guided drug repurposing: Identification of trypanocidal activity of clofazimine, benidipine and saquinavir

Bellera, Carolina L.; Balcazar, Darío Emmanuel; Vanrell, María Cristina; Casassa, Ana Florencia; Palestro, Pablo Hernán; Gavernet, Luciana; Labriola, Carlos; Gálvez, Jorge; Bruno-Blanch, Luis E.; Romano, Patricia Silvia; Carrillo, Carolina; Talevi, Alan

doi:10.1016/j.ejmech.2015.01.065

Cited by 65 publications

(55 citation statements)

References 77 publications

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“…OLZ was tested in Toxoplasma gondii due to the strong link demonstrated between toxoplasmosis and psychiatric disorders but it presented a low anti-toxoplasmic activity (72). Finally, CFZ was recently identified as a cruzipain inhibitor in T. cruzi with trypanocidal action, but it was also reported that cruzipain is not the only target for this compound (73).…”

Section: Discussionmentioning

confidence: 99%

Crystal violet structural analogues identified by in silico drug repositioning present anti-Trypanosoma cruzi activity through inhibition of proline transporter TcAAAP069

Sayé

Gauna

Valera-Vera

et al. 2019

Preprint

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BackgroundCrystal violet (CV) was used for several years in blood banks to eliminate the parasite Trypanosoma cruzi in endemic areas in order to prevent transfusion-transmitted Chagas disease. One mechanism of action described for CV involves inhibition of proline uptake. In T. cruzi, proline is essential for host cell infection and intracellular differentiation among other processes, and can be obtained through the proline permease TcAAAP069.Methodology/Principal FindingsCV inhibited proline transporter TcAAAP069 and parasites overexpressing this permease were 47-fold more sensitive to this compound than control parasites. Using CV as reference molecule, loratadine, cyproheptadine, olanzapine and clofazimine were identified as structurally related compounds to CV (structural analogues) by in silico drug repurposing through a similarity-based virtual screening protocol. All these already-approved drugs for clinical use inhibited TcAAAP069 activity with different efficacies and also presented trypanocidal action in epimastigotes, trypomastigotes and amastigotes of the Y strain. Additionally, loratadine, cyproheptadine and clofazimine showed trypanocidal effect on epimastigotes of the CL Brener and DM28c strains. Finally, a synergistic effect between benznidazole and the CV chemical analogues was evidenced by combination and dose-reduction indexes values in epimastigotes of the Y strain.Conclusions/SignificanceLoratadine, cyproheptadine and clofazimine inhibit TcAAAP069 proline transporter and also present trypanocidal effect against all T. cruzi life stages. These CV structural analogues could be a starting point to design therapeutic alternatives to treat Chagas disease by finding new indications for old drugs. This approach, called drug repurposing is a recommended strategy by the World Health Organization to treat neglected diseases, like Chagas disease, and combination therapy may improve the possibility of success of repositioned drugs.Author summaryChagas disease, caused by the parasite Trypanosoma cruzi, affects 7 million people worldwide. Despite there are two drugs available since 50 years ago, the therapy present severe side effects and is not effective in the chronic phase of the disease were most of the patients are diagnosed. Crystal violet (CV) was utilized as additive in blood banks to prevent transfusion-transmitted Chagas disease. Proline is involved in many pathways, like infection establishment and life cycle progression. In this work we first demonstrate that CV has the proline permease TcAAAP069 as one of its molecular targets. Then we search in a database of already-approved drugs for compounds that were structurally related to CV under the premise “similar structure, similar activity”. We identified three drugs that inhibit proline transport and present at least the same trypanocidal effect than benznidazole, the current treatment for Chagas disease. Finally we observed a synergistic effect with the multidrug combination therapy. Drug discovery is an expensive and time-consuming process and Chagas disease is associated with poverty. The discovery of new indications to old drugs, called drug repurposing, can facilitate a rapid and more profitable therapy application since preclinical trials and pharmacokinetic studies are already available.

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Section: Discussionmentioning

confidence: 99%

Crystal violet structural analogues identified by in silico drug repositioning present anti-Trypanosoma cruzi activity through inhibition of proline transporter TcAAAP069

Sayé

Gauna

Valera-Vera

et al. 2019

Preprint

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“…Both candidates significantly reduced the parasitemia and the number of T. cruzi cardiac nests in a murine acute model of T. cruzi infection. 33 Benidipine and Clofazimine were also able to reduce the parasite burden in cardiac and skeletal muscles of chronically infected mice compared with untreated mice as well as diminish the inflammatory process in these tissues. 34 …”

Section: The Etiologic Treatment With Benznidazole In Adult Patients mentioning

confidence: 94%

Drugs for the etiologic treatment of Chagas disease: Myths and Truths

Rivero¹,

Romano²

2016

ICFJ

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Chagas disease is a life-threatening illness caused by the protozoan parasite Trypanosoma cruzi. One of the characteristics of chronic chagasic infection is the parasitic persistence in cardiac and smooth muscle tissues. For this reason etiologic treatment of Chagas disease in all phases of infection is highly recommended. Despite the high number of trypanocidal drugs that have been discovered in the last years, only two compounds, Benznidazole and Nifurtimox remain as the unique drugs approved for Chagas treatment. Far from ideal, these drugs display low sensitivity and specificity resulting in limited applications, mainly in the onset of the acute phase. Thus there is an urgent need to validate new anti- T. cruzi drugs that can be applied even in the cases of chronic patients, those who today have no safe and effective treatment available. This paper reviews the most important compounds that have been tested in clinical trials and the results obtained to date.

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“…Next, the chemical similarity for these compounds was computed and those with similar structural and signature profiles were identified as possibly having the same molecular target, suggesting new indications for repurposed compounds. A related attempt to integrate signature and structure-based approaches for drug repurposing generated 62 vectors (per compound) for 147 drugs that are inhibitors of cruzipain, a parasitic cysteine protease [77]. The model trained using these vectors was then used to predict cruzipain inhibiting activity for 5000 compounds from Merck Index 12 th database [78].…”

Section: Gwas Based Gene Signatures For Repurposingmentioning

confidence: 99%

Integrative Omics for Informed Drug Repurposing: Targeting CNS Disorders

Shukla

Henkel

Alganem

et al. 2020

Preprint

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The treatment of CNS disorders, and in particular psychiatric illnesses, lacks disease-altering therapeutics for many conditions. This is likely due to regulatory challenges involving the high cost and slow-pace of drug development for CNS disorders as well as due to limited understanding of disease causality. Repurposing drugs for new indications have lower cost and shorter development timeline compared to that of de novo drug development. Historically, empirical drug-repurposing is a standard practice in psychiatry; however, recent advances in characterizing molecules with their structural and transcriptomic signatures along with ensemble of data analysis approaches, provides informed and cost-effective repurposing strategies that ameliorate the regulatory challenges. In addition, the potential to incorporate ontological approaches along with signature-based repurposing techniques addresses the various knowledge-based challenges associated with CNS drug development. In this review we primarily discuss signature-based in silico approaches to drug repurposing, and its integration with data science platforms for evidence-based drug repurposing. We contrast various in silico and empirical approaches and discuss possible avenues to improve the clinical relevance.These concepts provide a promising new translational avenue for developing new therapies for difficult to treat disorders, and offer the possibility of connecting drug discovery platforms and big data analytics with personalized disease signatures.3

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Computer-guided drug repurposing: Identification of trypanocidal activity of clofazimine, benidipine and saquinavir

Cited by 65 publications

References 77 publications

Crystal violet structural analogues identified by in silico drug repositioning present anti-Trypanosoma cruzi activity through inhibition of proline transporter TcAAAP069

Crystal violet structural analogues identified by in silico drug repositioning present anti-Trypanosoma cruzi activity through inhibition of proline transporter TcAAAP069

Drugs for the etiologic treatment of Chagas disease: Myths and Truths

Integrative Omics for Informed Drug Repurposing: Targeting CNS Disorders

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