Null
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB74174 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR12777742.fastq.gz | Fastqsanger.gz | |||
| ERR12777742_1.fastq.gz | Fastqsanger.gz | |||
| ERR12777742_2.fastq.gz | Fastqsanger.gz | |||
| ERR12777743.fastq.gz | Fastqsanger.gz | |||
| ERR12777743_1.fastq.gz | Fastqsanger.gz |
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Project description:P. falciparum is the deadliest causative agent of human malaria. This parasite has historically developed resistance to many drugs, including the current frontline treatments, so new therapeutic targets are needed Our previous work on guanine quadruplexes (G4s) in the parasite’s DNA and RNA has highlighted their influence on parasite biology, and also revealed G4 stabilising compounds as promising candidates for drug repositioning. In particular, quarfloxin, a former anticancer agent, kills blood-stage parasites at all developmental stages, with fast rates of kill and nanomolar potency. Here we explored the molecular mechanism of quarfloxin and its related derivative CX-5461. In vitro, both compounds bound to P. falciparum-encoded G4 sequences. In cellulo, quarfloxin was more potent than CX-5461, and could prevent establishment of blood-stage malaria in vivo in a murine model. CX-5461 showed clear DNA damaging activity, as reported in human cells, while quarfloxin caused weaker signatures of DNA damage. Both compounds caused transcriptional dysregulation in the parasite, but the affected genes were largely different, again suggesting different modes of action. Therefore, CX-5461 may act primarily as a DNA damaging agent in both Plasmodium parasites and mammalian cells, whereas the complete anti-malarial mode of action of quarfloxin may be parasite-specific, and remains elusive.
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Project description:Platinum-based compounds exert their anti-neoplastic effect through direct binding to DNA, which blocks fundamental cellular process ultimately resulting in apoptotic cell death. However, many ovarian cancers become refractory to treatment with platinum-based compounds. To improve the existing therapies for ovarian cancer, we sought to identify potent, nontoxic and specific drug candidates that have anti-neoplastic effects towards cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. Using a cell-based screening assay, we evaluated 56 compounds-derived from the Chinese medicinal plant, Phytolaccae, and one phytoaccagenin compound (Hu-17) was selected on the basis of its ability to dramatically decrease the viability of cisplatin-resistant SK-OV-3 cells.Using high-throughtput microarray system, we identified GO terms and pathway signatures enriched in Hu-17 and/or cisplatin treated SK-OV-3 cells.
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Project description:A novel compound exhibits potent anti-Candida albicans activity
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Project description:Treatment of Mycobacterium tuberculosis infections is a challenging task due to a growing number of resistant clinical isolates as well as an almost empty drug development pipeline. To identify new antibiotic hits, we screened a focused library of 400 synthetic compounds derived from a recently discovered molecule with promising anti-mycobacterial activity. A suite of more potent hit molecules was deciphered with sub-micromolar activity. Utilising tailored affinity-based probes for chemical proteomic investigations, we successfully pinpointed the mycolic acid transporter MmpL3 and two epoxide hydrolases, EphD and EphF, also linked to mycolic acid biosynthesis, as specific targets of the compounds. These targets were thoroughly and independently validated by activity assays, under- and overexpression, resistance generation, and proteomic studies. Structural refinement of the most potent hit molecules led to the development of a new lead compound that demonstrates enhanced biological activity in M. tuberculosis, low human cytotoxicity, and improved solubility and oral bioavailability − traits that are often challenging to achieve with anti-mycobacterial drugs. Overall, drug-likeness, as well as the dual mode of action, addressing the mycolic acid cell wall assembly at two distinct steps, holds significant potential for further in vivo applications.
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Project description:We introduce a family of multivalent peptidomimetic conjugates that modulate the activity of the androgen receptor (AR). Bioactive ethisterone ligands were conjugated to a set of sequence-specific peptoid oligomers. Certain multivalent peptoid conjugates enhance AR-mediated transcriptional activation. We identify a linear and a cyclic conjugate that exhibit potent anti-proliferative activity in LNCaP-abl cells, a model of therapy-resistant prostate cancer. The linear conjugate blocks AR action by competing for ligand binding. In contrast, the cyclic conjugate is active despite its inability to compete against endogenous ligand for binding to AR in vitro, suggesting a non-competitive mode of action. These results establish a versatile platform to design competitive and non-competitive AR modulators with potential therapeutic significance. We use microarray analysis to further elucidate the mechanism of AR antagonism and show that the compounds (cyc and n=8) are distinct. We used microarray analysis to see genone-wide effects on LNCaP-abl cells with moduators of AR activity LNCaP-abl cells were treated with compound and RNA was extracted and hybridized on Affymetrix microarrays Treatments: Vehicle is just Ethanol treated LNCaP-abl cells that were used as a control. n=8 and cyc are peptoid conjugates that modulate AR activity. n=8 is linear and cyc is a cyclic compounds. We wanted to look at gene expression when LNCaP-abl cells were treated with these compounds to show that they are distinct. C3 is a small molecule that inhibits the interaction between AR and beta-catenin (co-regulator protein). Initial results with this compound show potent anti-proliferative activity in LNCaP-abl cells and we wanted to further investigate the mechanism of action of this compound.
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Project description:In a phenotypic screening approach of novel molecules composed of a synergistic combination of phthalimide, benzimidazole, and triazole scaffolds we discovered compounds with potent anti-leishmanial activity. The resulting early-lead compound PHT-39, which contains a trifluoromethyl substitution, demonstrated the highest efficacy in a Leishmania infantum intramacrophage assay, with an EC50 of 1.2+/- 3.2 μM.Cytotoxicity testing of PHT-39 in Hep-G2 cells indicated high selectivity of over 90-fold. To investigate the mechanism of action we carried out experiments in Trypanosoma brucei, which is also sensitive to PHT-39. Here we used a genome-wide RNAi library approach (PMID: 22278056; PMID: 21363968) to detect sensitivity determinants. This high-throughput phenotyping approach identified sensitivity determinants for PHT-39, which included a P-type ATPase that is crucial for the uptake of miltefosine and amphotericin, strongly indicating a shared route for cellular entry.
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Project description:Most malaria drug development focuses on parasite stages detected in red-blood cells even though to achieve eradication next-generation drugs active against both erythrocytic and exo-erythrocytic forms would be preferable. We applied a multifactorial approach to a set of >4,000 commercially available compounds with previously demonstrated blood stage activity (IC50 < 1 µM), and identified chemical scaffolds with potent activity against both forms. From this screen, we identified an imidazolopiperazine scaffold series that was highly enriched among compounds active against Plasmodium liver stages. Our orally bioavailable lead imidazolopiperazine confers complete causal prophylactic protection (15 mg/kg) in rodent models of malaria and shows potent in vivo blood-stage therapeutic activity. The open source chemical tools resulting from our effort provide starting points for future drug discovery programs, as well as opportunities for researchers to investigate the biology of exo-erythrocytic forms.
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Project description:Most malaria drug development focuses on parasite stages detected in red-blood cells even though to achieve eradication next-generation drugs active against both erythrocytic and exo-erythrocytic forms would be preferable. We applied a multifactorial approach to a set of >4,000 commercially available compounds with previously demonstrated blood stage activity (IC50 < 1 M-BM-5M), and identified chemical scaffolds with potent activity against both forms. From this screen, we identified an imidazolopiperazine scaffold series that was highly enriched among compounds active against Plasmodium liver stages. Our orally bioavailable lead imidazolopiperazine confers complete causal prophylactic protection (15 mg/kg) in rodent models of malaria and shows potent in vivo blood-stage therapeutic activity. The open source chemical tools resulting from our effort provide starting points for future drug discovery programs, as well as opportunities for researchers to investigate the biology of exo-erythrocytic forms. Genome DNA from IP resistant strains vs. Reference 3D7 or Dd2
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