Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Identification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria

ABSTRACT: Malaria remains a global health threat as drug resistance threatens treatment programs. We identified a piperidine carboxamide (SW042) with anti-malarial activity by phenotypic screening. Selection of SW042-resistant Plasmodium falciparum (Pf) parasites revealed point mutations in the Pf_proteasome beta5 active-site. A potent analog (SW584) showed efficacy in a mouse model of human malaria after oral dosing. SW584 had a low propensity to generate resistance (Minimum Inoculum of Resistance >109) and was synergistic with dihydroartemisinin. Pf_proteasome purification was facilitated by His8-tag introduction onto beta7. Inhibition of Pfbeta5 correlated with parasite killing, without inhibiting the human proteasome or showing cytotoxicity. The Pf_proteasome_SW584 cryo-EM structure showed SW584 bound non-covalently distal from the catalytic threonine, in an unexplored pocket at the beta5/beta6/beta3 subunit interface that shows species differences between Pf and human proteasomes. Identification of a reversible, species selective, orally active series with low resistance propensity, provides a path for drugging this essential target.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human) Plasmodium Falciparum (isolate 3d7)

SUBMITTER: Andrew Lemoff

LAB HEAD: Margaret A. Phillips

PROVIDER: PXD053252 | Pride | 2024-07-30

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	LUM1_1032594.mgf	Mgf
	LUM1_1032594.msf	Msf
	LUM1_1032594.raw	Raw
	LUM2_1060117.mgf	Mgf
	LUM2_1060117.msf	Msf

Items per page:

1 - 5 of 6

Similar Datasets

Identification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria

Project description:Malaria remains a global health threat as drug resistance threatens treatment programs. We identified a piperidine carboxamide (SW042) with anti-malarial activity by phenotypic screening. Selection of SW042-resistant Plasmodium falciparum (Pf) parasites revealed point mutations in the Pf_proteasome 5 active-site. A potent analog (SW584) showed efficacy in a mouse model of human malaria after oral dosing. SW584 had a low propensity to generate resistance (Minimum Inoculum of Resistance >109) and was synergistic with dihydroartemisinin. Pf_proteasome purification was facilitated by His8-tag introduction onto 7. Inhibition of Pf5 correlated with parasite killing, without inhibiting the human proteasome or showing cytotoxicity. The Pf_proteasome_SW584 cryo-EM structure showed SW584 bound non-covalently distal from the catalytic threonine, in an unexplored pocket at the 5/6/3 subunit interface that shows species differences between Pf and human proteasomes. Identification of a reversible, species selective, orally active series with low resistance propensity, provides a path for drugging this essential target.

2024-07-30 | PXD052762 | Pride

Identification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria

2024-07-30 | PXD052830 | Pride

Cytosine methylation of tRNA in Plasmodium falciparum disrupts translational homeostasis to prime for sexual commitment

Project description:Malaria parasites have evolved a well-adjusted developmental program to progress through the complex life cycle in the human and mosquito host. Here we identify cytosine methylation of tRNAAsp (GTC) as being critical to maintain stable protein synthesis under cellular stress. Using conditional knock out of a member of the DNA methyltransferases family called Pf-DNMT2, RNA bisulfite sequencing demonstrates the selective cytosine methylation of this enzyme of tRNAAsp (GTC) at position C38. Although no growth defect on parasite asexual proliferation was observed, Pf-DNMT2 KO parasites show a striking increase in their sexual commitment and an increased sensitivity to Dihydroartemisinin. In mutant parasites we observe a dramatic decrease of tRNAAsp (GTC) when compared to non-stressed parasites and mass spectrometry analysis shows the selective downregulation of proteins with GAC codon bias. Here we identify an epitranscriptomic mechanism that safeguards protein translation and homeostasis of sexual commitment during cellular stress in malaria parasites

2022-02-13 | PXD024769 | Pride

Transcription profiling of PfSPZ Malaria Vaccine trial subjects receiving a 3-dose regimen in a malaria endemic region

Project description:The Sanaria® PfSPZ Vaccine can confer sterilizing protection against liver stage infection by Plasmodium falciparum (Pf) in malaria naïve individuals. The vaccine consists of aseptically purified irradiated Pf sporozoites. Vaccinees received 3 doses of 1.8 X 106 irradiated sporozoites. Efficacy was measured by challenged by controlled human malaria infections (CHMI), and against naturally occurring Pf Infections in Malian adults during the malaria transmission season

2022-08-20 | GSE211599 | GEO

Transcription profiling of PfSPZ Malaria Vaccine trial subjects in a malaria endemic region

Project description:The Sanaria® PfSPZ Vaccine can confer sterilizing protection against liver stage infection by Plasmodium falciparum (Pf) in malaria naïve individuals. The vaccine consists of aseptically purified irradiated Pf sporozoites. The PfSPZ Vaccine trial in Mali was the first to evaluate the safety and efficacy of this vaccine in a malaria endemic region. Vaccinees received five doses of 2.7 X 105 irradiated sporozoites and the efficacy was measured against naturally occurring Pf Infections in Malian adults during the malaria transmission season.

2017-01-01 | GSE86308 | GEO

Molecular Hallmarks of Naturally Acquired Immunity to Malaria

Project description:Immunity to malaria can be acquired through natural exposure to Plasmodium falciparum (Pf), but only after years of repeated infections. Typically, this immunity is acquired by adolescence and confers protection against disease, but not Pf infection per se. Efforts to understand the mechanisms of this immunity are integral to the development of a vaccine that would mimic the induction of adult immunity in children. The current study applies transcriptomic analyses to a cohort from the rural village of Kalifabougou, Mali, where Pf transmission is intense and seasonal. Signatures that correlate with protection from malaria may yield new hypotheses regarding the biological mechanisms through which malaria immunity is induced by natural Pf infection. The resulting datasets will be of considerable value in the urgent worldwide effort to develop a malaria vaccine that could prevent more than a million deaths annually. 108 samples; paired pre- and post-challenge for 54 individuals 198 samples; paired pre- and post-challenge for 99 individuals

2013-11-08 | E-GEOD-52166 | biostudies-arrayexpress

Plasmodium-specific atypical memory B cells upregulate markers of activation and co-stimulatory molecules indicative of cellular interaction with T cells in response to a febrile malaria infection in children and adults.

Project description:In naturally acquired immunity to malaria, antibodies that reliably protect are only acquired after years of repeated Plasmodium falciparum (Pf) infections. We have shown in Mali that this inefficiency in humoral immunity to malaria is associated with a large expansion of CD21loCD27- ‘atypical’ B cells (atBCs). The function of atBCs remains elusive, as they exhibit altered B cell receptor (BCR) signaling and when activated fail to secrete cytokines and antibodies. We set out to study the participation and function of malaria-specific atBCs during the immune response to a febrile malaria infection. Here, we show in a Mali cohort spanning infants to adults, that atBCs frequencies within the malaria and influenza-specific MBC compartment are comparable to the overall atBC frequency, showing that atBCs are not predominantly expanded within Pf-specific B cells. We performed a transcriptional analysis of Pf- and influenza-specific atBCs, actBC and MBCs and show that CXCL16, IL-6, IL-10, TNFα, IL12R and IL12R are uniquely upregulated in Pf-specific atBCs. Comparative transcriptomic and flow cytometric analysis before and after an acute malaria infection showed that after malaria, Pf-specific atBCs are transcriptionally most like the actBC subset, sharing many common features, such as activation of intracellular signaling pathways and expression of high levels of T-bet, FcRL5, Ki67 and CD86. Unique to Pf-specific atBCs was an upregulation of IL-5RA, CD38, CXCR3, TLR7, 9 and 10 after a febrile malaria episode. Our data shows that atBCs exhibit a surface marker profile that could facilitate cellular interaction with T cells in secondary lymphoid tissues.

2022-06-01 | GSE183744 | GEO

Molecular Hallmarks of Naturally Acquired Immunity to Malaria

2013-11-08 | GSE52166 | GEO

Transcription profiling of PfSPZ Vaccine trial subjects (US, malaria naïve) receiving a 3-dose or 5-dose regimen

Project description:The Sanaria® PfSPZ Vaccine can confer sterilizing protection against liver stage infection by Plasmodium falciparum (Pf) in malaria naïve individuals. The vaccine consists of aseptically purified irradiated Pf sporozoites. Vaccinees received either 3 doses of 1.8M irradiated sporozoites or 5 doses of 270K. Efficacy was measured by challenged by controlled human malaria infections (CHMI) at 3 weeks and 24 weeks after the last vaccine dose

2022-08-22 | GSE211626 | GEO

single-cell RNA-sequencing on human naïve and memory CD4+ T cells during Plasmodium falciparum infection

Project description:Plasmodium falciparum (Pf) malaria causes high rates of morbidity and mortality and lacks an effective vaccine. Clinical immunity develops in residents of malaria endemic regions which confers reduced clinical symptoms during infection and protects against severe disease. We hypothesized that understanding the immune mechanisms of clinical immunity could inform vaccine design to improve efficacy. We compared the peripheral blood cellular and humoral immune responses during Pf malaria infection between clinically susceptible and protected participants from a malaria endemic region in Malawi during a prospective 18-month longitudinal study. Participant classifications were defined by the number of recurrent clinical malaria episodes with susceptible participants having more than three while protected less than one episode during the study period. Protected participants exhibited higher immunoglobulin G (IgG) breadth and titers against Pf antigens, and greater antibody (Ab)-dependent Pf opsonization compared to susceptible participants, consistent with our classifications. Using high dimensional mass cytometry (CyTOF) and spectral flow cytometry, and single-cell transcriptomic analyses, we identified expanded memory CD4+ T cell clonotypes in the blood of protected participants undergoing malaria infection. These cells express a strong cytolytic T helper 1 effector program with transcripts encoding granzymes (A, B, H, M), granulysin, NKG7 and the ZEB2 master transcriptional regulator of terminally differentiated effector T cells. ZEB2+ memory CD4+ T cells were CD39hiTIGIThi and expressed multiple chemotactic and inhibitory receptors. Yet, their levels of several chemokine and checkpoint inhibitory receptors were reduced in protected compared to susceptible individuals. We propose that clonally expanded ZEB2+ cytolytic memory CD4+ Th1 cells could represent essential contributors to clinical immunity against Pf malaria infection.

2021-08-28 | GSE182536 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data