Phenotypic, chemical and functional characterization of cyclic nucleotide phosphodiesterase 4 (PDE4) as a potential anthelmintic drug target

Long, Ting; Rojo‐Arreola, Liliana; Shi, Da; El-Sakkary, Nelly; Jarnagin, Kurt; Rock, Fernando; Meewan, Maliwan; Rascón, Alberto A.; Lin, Lin; Cunningham, Kathryn A.; Lemieux, George A.; Podust, L.M.; Abagyan, Ruben; Ashrafi, Kaveh; McKerrow, James H.; Caffrey, Conor R.

doi:10.1371/journal.pntd.0005680

Cited by 37 publications

(51 citation statements)

References 113 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The resulting phenotypes were classified using a previously described nomenclature that records the many non-exclusive changes (descriptors) that can occur in the parasite in response to chemical insult. Each descriptor is converted into a value from 0 (no effect) to 4 (maximal effect) to allow for comparisons of effects on the parasite between compounds [40][41][42][43]. For consistency, we consider a score of 2 to be the minimum for a compound to be considered active.…”

Section: Bioactivities and Structure-activity Relationship (Sar)mentioning

confidence: 99%

“…Each descriptor was given a value of 1 and these were added up to yield a "severity score" with a maximum of 4. Evidence of degeneracy or death was awarded a value of 4 for adult parasites specifically, the inability to adhere to the bottom of the well using oral or ventral suckers was given a score of 1 and damage to the tegument (surface) was awarded a value of 4 on the understanding that such damage in vivo would compromise survival [42,43]. Scores were averaged across the two experiments.…”

Section: General Synthetic Procedures For Final Compounds 6(a-u')mentioning

confidence: 99%

See 1 more Smart Citation

Synthesis and Bioactivity of Phthalimide Analogs as Potential Drugs to Treat Schistosomiasis, a Neglected Disease of Poverty

et al. 2020

Self Cite

View full text Add to dashboard Cite

The neglected tropical disease, schistosomiasis, is caused by trematode blood flukes of the Schistosoma genus and infects approximately 200 million people worldwide. With just one partially effective drug available for disease treatment, new drugs are urgently needed. Herein, a series of 47 phthalimide (Pht) analogues possessing high-value bioactive scaffolds (i.e., benzimidazole and 1,2,3,-triazoles) was synthesized by click-chemistry. Compounds were evaluated for anti-schistosomal activity in culture against somules (post-infective larvae) and adults of Schistosoma mansoni, their predicted ADME (absorption, distribution, metabolism, and excretion) properties, and toxicity vs. HepG2 cells. The majority showed favorable parameters for surface area, lipophilicity, bioavailability and Lipinski score. Thirteen compounds were active at 10 µM against both somules and adults (6d, 6f, 6i-6l, 6n-6p, 6s, 6r', 6t' and 6w). Against somules, the majority caused degeneracy and/or death after 72 h; whereas against adult parasites, five compounds (6l, 6d, 6f, 6r' and 6s) elicited degeneracy, tegumental (surface) damage and/or death. Strongest potency against both developmental stages was recorded for compounds possessing n-butyl or isobutyl as a linker, and a pentafluorophenyl group on triazole. Apart from five compounds for which anti-parasite activity tracked with toxicity to HepG2 cells, there was apparently no toxicity to HepG2 cells (EC 50 values ≥50 µM). The data overall suggest that phthaloyl-triazole compounds are favorable synthons for additional studies as anti-schistosomals.

show abstract

Section: Bioactivities and Structure-activity Relationship (Sar)mentioning

confidence: 99%

Section: General Synthetic Procedures For Final Compounds 6(a-u')mentioning

confidence: 99%

Synthesis and Bioactivity of Phthalimide Analogs as Potential Drugs to Treat Schistosomiasis, a Neglected Disease of Poverty

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…A dose of 600 infective larvae (cercariae) was used to infect hamsters. The acquisition, preparation and in vitro maintenance of S. mansoni post-infective larvae (schistosomula or somules) and adults have been already described 5,50,51 . Vertebrate animal maintenance and handling at the University of California San Diego Animal Care Facility were in accordance with protocols approved by the university's Institutional Animal Care and Use Committee (IACUC).…”

Section: Cytotoxicity Assay On Bovine Spermatozoa Semen Samples Werementioning

confidence: 99%

“…Phenotypic screens with somules were performed as described 5,50,51 . Initially, 100 μL Basch medium 52 , 100 U/ml penicillin, 100 mg/ml streptomycin, 4% heat-inactivated FBS (Corning Mediatech) and 1 μl compound in DMSO were added to clear, 96-well round-bottomed plates (Costar cat.# 3367).…”

Section: Cytotoxicity Assay On Bovine Spermatozoa Semen Samples Werementioning

confidence: 99%

“…Schistosome phenotypic responses were recorded employing a series of 'descriptors, ' such as rounding, degeneration, overactivity, loss of translucency and changes in motility, as described previously 5,50,51,53 . To allow for comparisons of compound activity, each descriptor was awarded a value of 1 and these were added up to a maximum 'severity score' of 4.…”

Section: Cytotoxicity Assay On Bovine Spermatozoa Semen Samples Werementioning

confidence: 99%

See 1 more Smart Citation

Novel and selective inactivators of Triosephosphate isomerase with anti-trematode activity

Ferraro

Corvo

Bergalli

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

Trematode infections such as schistosomiasis and fascioliasis cause significant morbidity in an estimated 250 million people worldwide and the associated agricultural losses are estimated at more than US$ 6 billion per year. Current chemotherapy is limited. Triosephosphate isomerase (TIM), an enzyme of the glycolytic pathway, has emerged as a useful drug target in many parasites, including Fasciola hepatica TIM (FhTIM). We identified 21 novel compounds that selectively inhibit this enzyme. Using microscale thermophoresis we explored the interaction between target and compounds and identified a potent interaction between the sulfonyl-1,2,4-thiadiazole (compound 187) and FhTIM, which showed an ic 50 of 5 µM and a K d of 66 nM. In only 4 hours, this compound killed the juvenile form of F. hepatica with an ic 50 of 3 µM, better than the reference drug triclabendazole (TCZ). Interestingly, we discovered in vitro inhibition of FhTIM by TCZ, with an IC 50 of 7 µM suggesting a previously uncharacterized role of FhTIM in the mechanism of action of this drug. Compound 187 was also active against various developmental stages of Schistosoma mansoni. The low toxicity in vitro in different cell types and lack of acute toxicity in mice was demonstrated for this compound, as was demonstrated the efficacy of 187 in vivo in F. hepatica infected mice. Finally, we obtained the first crystal structure of FhTIM at 1.9 Å resolution which allows us using docking to suggest a mechanism of interaction between compound 187 and TIM. In conclusion, we describe a promising drug candidate to control neglected trematode infections in human and animal health.

show abstract

Drug Discovery Strategies for Neglected Tropical Diseases: Repurposing Knowledge, Mechanisms and Therapeutics to Increase Discovery Efficiency

Swinney¹,

Pollastri

2019

Neglected Tropical Diseases

View full text Add to dashboard Cite

Phenotypic, chemical and functional characterization of cyclic nucleotide phosphodiesterase 4 (PDE4) as a potential anthelmintic drug target

Abstract: Background

Cited by 37 publications

References 113 publications

Synthesis and Bioactivity of Phthalimide Analogs as Potential Drugs to Treat Schistosomiasis, a Neglected Disease of Poverty

Synthesis and Bioactivity of Phthalimide Analogs as Potential Drugs to Treat Schistosomiasis, a Neglected Disease of Poverty

Novel and selective inactivators of Triosephosphate isomerase with anti-trematode activity

Drug Discovery Strategies for Neglected Tropical Diseases: Repurposing Knowledge, Mechanisms and Therapeutics to Increase Discovery Efficiency

Contact Info

Product

Resources

About