Comparative Proteomics Reveals Characteristic Proteins on Praziquantel-resistance in<i>Schistosoma mansoni</i>

Pinto-Almeida, António; Mendes, Tiago Manuel Fernandes; Ferreira, Patricia; Belo, Silvana; Anibal, Freitas; Allegretti, Silmara Marques; Carrilho, Emanuel; Afonso, Ana

doi:10.1101/314724

Cited by 7 publications

(7 citation statements)

References 87 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although the mechanism of action of PZQ and the molecular basis of juvenile resistance is not yet understood, previous studies have identified gene products that may play a role in both [18][19][20]39,40]. We have examined the differential regulation of a number of these genes previously and identified stress related genes that are differentially regulated in response to PZQ exposure in vitro [19] and in vivo [20].…”

Section: Expression Analysis Of Transcripts Related To Pzq-selectionmentioning

confidence: 99%

“…Pinto-Almeida et al [40] revealed proteins associated with S. mansoni PZQ resistance through comparative proteomics. PZQ resistance was generated in a fully susceptible isogenic S. mansoni strain treated with 0.3 μM PZQ and compared to a fully susceptible strain using high throughput LC-MS/MS identification of protein spots after 2-dimensional gel electrophosesis.…”

Section: Expression Analysis Of Transcripts Related To Pzq-selectionmentioning

confidence: 99%

See 1 more Smart Citation

Transcriptomic analysis of reduced sensitivity to praziquantel in Schistosoma mansoni

Sanchez

Cupit

et al. 2019

Molecular and Biochemical Parasitology

View full text Add to dashboard Cite

Schistosomiasis is an intravascular parasitic infection estimated to affect over 206 million people, the majority of whom live in Africa where the trematode worms Schistosoma mansoni and Schistosoma haematobium are the major causative agents. While a number of drugs have been used to treat schistosomiasis, praziquantel (PZQ) is the only one that is widely available, relatively cheap, and easy to use. The reliance on a single drug for the treatment of such a prevalent disease is a cause for concern due to the potential for resistance to render PZQ ineffective. In this study, we examine the transcriptome of three generations of a laboratory strain of S. mansoni (PR1) whose susceptibility to PZQ has been diminished across 9 passages through exposure to increasing sub-lethal doses of the drug. Miracidial susceptibility was significantly reduced after exposure to 2 × 50 mg/Kg PZQ during the first passage. Susceptibility of worms in vivo was first assessed during passage 5 when mice infected with PZQ-selected schistosomes were dosed with a lethal dose of 3 × 300 mg/kg PZQ resulting in only a 10% reduction in worm number compared to control treatment. The emergence of reduced sensitivity was marked by a shift in sex ratio from a predominantly male to a female population, a reduction in the length of females and ultimately the loss of the PZQ-selected line after passage 9. Analysis of differentially regulated transcripts did not suggest that any particular gene product or pathway was associated with drug resistance suggesting either a loss of function mutation to a single gene or an epistatic interaction of multiple gene products as the underlying cause of reduced susceptibility.

show abstract

Section: Expression Analysis Of Transcripts Related To Pzq-selectionmentioning

confidence: 99%

Section: Expression Analysis Of Transcripts Related To Pzq-selectionmentioning

confidence: 99%

Transcriptomic analysis of reduced sensitivity to praziquantel in Schistosoma mansoni

Sanchez

Cupit

et al. 2019

Molecular and Biochemical Parasitology

View full text Add to dashboard Cite

show abstract

“…Resistant isolates of Schistosoma spp. have been generated in the laboratory by several laboratories [88][89][90][91][92][93][94]. This is often achieved through the repeated, sub-lethal dosing with PZQ.…”

Section: Resistance To Pzq Could Arisementioning

confidence: 99%

The Mechanism of Action of Praziquantel: Six Hypotheses

Thomas

Timson

2018

CTMC

View full text Add to dashboard Cite

Despite being one of the most commonly used drugs, the molecular mechanism of action of the anthelmintic praziquantel remains unknown. There are some unusual features of this drug. Critically, widespread resistance to praziquantel has not developed despite decades of use. Here, we set out some challenges in praziquantel research and propose some provocative hypotheses to address these. We suggest that praziquantel may have multiple pharmacologically relevant targets and the effects on these may synergise to produce an overall, detrimental effect on the parasite. Praziquantel also acts on a number of host proteins and we propose that these actions are important in the drug’s overall mechanism. Although the drug is largely used in the treatment of human and domestic animal worm infections, there is a considerable “grey literature” along with some academic studies which may have been overlooked. It appears that praziquantel may be effective against hydra. It may also be effective against some unicellular parasites such as Giardia spp. Further, scientific work on these understudied areas may be useful in understanding the molecular mechanism in Trematoda. The lack of widespread resistance suggests that praziquantel may act, at least in part, on a protein-protein interaction. Altered drug metabolism or enhanced drug efflux are the most likely ways resistance may arise. There is a critical need to understand the biochemical pharmacology of this drug in order to inform the discovery of the next generation of anthelmintic drugs.

show abstract

“…There is no effective vaccine currently 3,9 . Other chemotherapy alternatives include oxamniquine and metrifonate, although these have some setbacks, such as being ineffective against all life stages of the parasite and severe side effects, which is why praziquantel is recommended [10][11][12][13][14][15][16][17] . Although praziquantel is effective, relatively safe and low cost, laboratory and field studies have shown the emergence of a resistant parasite strain in certain regions.…”

Section: Introductionmentioning

confidence: 99%

Structural, functional and docking analysis against Schistosoma mansoni dihydroorotate dehydrogenase for potential chemotherapeutic drugs

Otarigho

2019

F1000Res

View full text Add to dashboard Cite

Background: Praziquantel, as the only drug for the treatment of schistosomiasis, is under serious threat due to the emergence of resistant strains of Schistosoma species. There is an urgent need to search for alternative chemotherapy to supplement or complement praziquantel. Schistosoma dihydroorotate dehydrogenase (DHODH) has been recommended as a druggable target for schistosomiasis chemotherapy. The development of novel molecular modeling approaches, alongside with computational tools and rapid sequencing of pathogen genomes, have facilitated drug discovery. Therefore, the aim of this study was to employ computational approaches to screen compounds against Schistosoma mansoni DHODH. Methods: In this study, DHODH was used to blast on the latest version of DrugBank that contained 12,110 compounds, resulting in 26 drugs that can bind. Results: In silico docking shows that 13 drugs can bind strongly with an estimated free energy of binding, total intermolecular energy and estimated inhibition constant (Ki) greater than or equal to -8.6 kcal/mol, -8.12 kcal/mol and 1.12 µM, respectively. These compounds include the approved drugs manitimus, capecitabine, brequinar analog and leflunomide. Conclusions: These results indicate that these drugs have the potential for use in the control of schistosomiasis in the future.

show abstract

Comparative Proteomics Reveals Characteristic Proteins on Praziquantel-resistance inSchistosoma mansoni

Cited by 7 publications

References 87 publications

Transcriptomic analysis of reduced sensitivity to praziquantel in Schistosoma mansoni

Transcriptomic analysis of reduced sensitivity to praziquantel in Schistosoma mansoni

The Mechanism of Action of Praziquantel: Six Hypotheses

Structural, functional and docking analysis against Schistosoma mansoni dihydroorotate dehydrogenase for potential chemotherapeutic drugs

Contact Info

Product

Resources

About