Drug target identification of compound M1.HCl
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ABSTRACT:
PROVIDER: PRJEB61247 | ENA |
REPOSITORIES: ENA
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Project description:To combat the global burden of malaria, development of new drugs to replace or complement current therapies are urgently required. As drug resistance to existing treatments and clinical failures continue to rise, compounds targeting multiple life cycle stages and species need to be developed as a high priority. Here we show that the compound MMV1557817 is a nanomolar inhibitor of both Plasmodium falciparum and Plasmodium vivax aminopeptidases M1 and M17, leading to inhibition of end stage haemoglobin digestion in asexual parasites. Multi-stage analysis confirmed that MMV1557817 can also kill sexual stage P. falciparum, while cross-resistance studies confirmed the compound targets a mechanism of action distinct to current drug resistance mechanisms. Analysis of cross reactivity to homologous human enzymes shows the compound exhibits a high level of selectivity, whilst safety as well as druggability was confirmed in the murine model P. berghei. MMV1557817-resistant P. falciparum parasites displayed only low-level resistance (<3-fold) and exhibited a slow growth rate that was quickly outcompeted by wild type parasites. MMV1557817-resistant parasites digest significantly more haemoglobin and possess a mutation in PfA-M17 that induces partial destabilization of the PfA-M17 homohexamer, resulting in high-level resistance to specific PfA-M17 inhibition, but enhanced sensitivity to specific PfA-M1 inhibition, and importantly, these parasites were highly sensitive to artemisinin. Overall, these results confirm MMV1557817 as a potential lead compound for further drug development and highlight the potential of dual inhibition of M1 and M17 as an effective multi-species drug targeting strategy.
2024-05-06 | PXD046006 | Pride
Project description:All current treatments for malaria are threatened by drug resistance, and new drug candidates that act via novel mechanisms are urgently needed. Here, we describe MIPS2673, an inhibitor of the Plasmodium M1 alanyl metalloaminopeptidase, which displays excellent in vitro antimalarial activity with no significant host cell toxicity. Biochemical assays revealed potent inhibition of recombinant Plasmodium falciparum (PfA-M1) and Plasmodium vivax (Pv-M1) M1 metalloaminopeptidases, with selectivity over other Plasmodium and human aminopeptidases. Orthogonal chemoproteomic methods based on thermal stability and limited proteolysis reproducibly identified PfA-M1 as the sole target of MIPS2673 in parasites from approximately 2,000 detected proteins. Furthermore, the limited proteolysis approach enabled estimation of the binding site on PfA-M1 to within ~5 Å of that determined by X-ray crystallography. Functional investigation by untargeted metabolomics further demonstrated that MIPS2673 inhibits the key role of PfA-M1 in haemoglobin digestion. Combined, our unbiased target deconvolution strategies confirmed the on-target activity of a PfA-M1 inhibitor, and validated selective inhibition of this enzyme as a promising multi-stage and cross-species antimalarial strategy.
2024-06-16 | PXD044125 | Pride
Project description:Malaria eradication requires the development of new drugs to combat drug-resistant parasites. The search for new chemical scaffolds that target novel pathways of the human malaria parasite Plasmodium falciparum is of highest priority. We identified bisbenzylisoquinoline alkaloids isolated from Cocculus sp. (trilobine derivatives) as active in the nanomolar range against P. falciparum blood stages. Synthesis of a library of 94 hemi-synthetic derivates allowed us to identify compound 84 (c-84) that kills multi-drug resistant clinical isolates in the nanomolar range (median IC50 ranging from 35-88nM). Efforts were made to obtain compounds with significantly improved preclinical properties. Out of those, compound 125 (c-125) delays the onset of parasitemia in P. berghei infected mice and inhibits P. falciparum transmission stages in vitro (culture assays) and in vivo using membrane feeding assay in the Anopheles stephensi vector. C-125 also impairs P. falciparum development in sporozoite-infected hepatocytes, in the low micromolar range. Finally, we used a chemical pull-down to identify potential protein targets of this chemical family. Our mass spectrometry analysis identified the parasite interactome with trilobine alkaloid, allowing us to identify protein partners belonging to metabolic pathways that have not been previously targeted by antimalarial drugs or implicated in drug-resistance mechanisms in malaria parasites.
2023-01-01 | PXD036288 | Pride
Project description:We previously identified small molecules that fit into a BRCA1-binding pocket within estrogen receptor-alpha (ER), mimic the ability of BRCA1 to inhibit ER activity (“BRCA1-mimetics”), and overcome antiestrogen resistance. One such compound, the hydrochloride salt of NSC35446 (“NSC35446.HCl”), also inhibited growth of antiestrogen-resistant LCC9 tumor xenografts. The purpose of this study was to investigate the down-stream effects of NSC35446.HCl and its mechanism of action. Methods: Here, we studied antiestrogen-resistant (LCC9, T47DCO, MCF-7/RR, LY2), ER-negative (MDA-MB-231, HCC1806, MDA-MB-468), and antiestrogen-sensitive (MCF-7) cell lines. Techniques utilized include RNA-seq, qRT-PCR, cell growth analysis, cell-cycle analysis, Western blotting, luciferase reporter assays, TUNEL assays, in-silico analysis of the IKKB gene, and ChIP assays. Results: NSC35446.HCl inhibited proliferation and induced apoptosis in antiestrogen resistant LCC9, T47DCO, MCF-7/RR, and LY2 cells but not in ER-negative breast cancer cell lines. IKKB (IKKβ, IKBKB), an upstream activator of NF-B, was identified as a BRCA1-mimetic-regulated gene, based on an RNA-seq analysis; and NSC35446.HCl inhibited IKKB mRNA and protein expression in LCC9 cells. NSC35446.HCl also inhibited NF-B activity and expression of NF-B target genes. In-silico analysis of the IKKB promoter identified nine estrogen response element (ERE) half-sites and one ERE-like full-site. ChIP assays revealed that ER was recruited to the ERE-like full-site and five of the nine half-sites and that ER recruitment was inhibited by NSC35446.HCl in LCC9 and T47DCO cells. Conclusions: These studies identify functional EREs in the IKKB promoter and identify IKKB as an NSC35446.HCl-regulated gene; and they suggest that NF-B and IKKB, which were previously linked to antiestrogen resistance, are targets for NSC35446.HCl in reversing antiestrogen resistance.
2017-07-21 | GSE101691 | GEO
Project description:This project is to investgate the effect of M1 compound in gddy mice
2020-04-02 | PXD008431 | Pride
Project description:Transcription time course of Plasmodium falciparum parasite asexual blood stage progression in the presence of antimalarial drug CID5750730 (Compound C)
2022-05-13 | GSE202876 | GEO
Project description:This study provides an evaluation of changes in gene expression associated with chlorpromazine HCl treatment of rat hepatocytes in vitro. Primary rat hepatocytes were treated for 24 and 48 hours with two doses (0.8 uM and 20 uM) of chlorpromazine HCl and 1% DMSO vehicle control. Five replicates of each treatment were performed. Cells were then extracted and RNA processed for microarray analysis. This series is part of a SuperSeries in which primary rat hepatocytes were treated with two doses of ten chemical compounds (and corresponding vehicle controls) for 24 and 48 hours. Each compound/vehicle treatment group was an individual study performed at different times. Each study was analyzed separately and themes common between studies were reported. Time Course/Dose Response
2012-08-28 | E-GEOD-40341 | biostudies-arrayexpress
Project description:Paenibacillus agaridevorans isolate:HCL Genome sequencing
| PRJNA670333 | ENA
Project description:This study provides an evaluation of changes in gene expression associated with chlorpromazine HCl treatment of rat hepatocytes in vitro. Primary rat hepatocytes were treated for 24 and 48 hours with two doses (0.8 uM and 20 uM) of chlorpromazine HCl and 1% DMSO vehicle control. Five replicates of each treatment were performed. Cells were then extracted and RNA processed for microarray analysis.
2012-08-28 | GSE40341 | GEO