PXD052830 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Identification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria |
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. |
HostingRepository | PRIDE |
AnnounceDate | 2024-10-22 |
AnnouncementXML | Submission_2024-10-22_06:51:48.347.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Andrew Lemoff |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; scientific name: Plasmodium falciparum (isolate 3D7); NCBI TaxID: 36329; |
ModificationList | monohydroxylated residue; iodoacetamide derivatized residue |
Instrument | Q TRAP |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2024-06-04 07:55:43 | ID requested | |
1 | 2024-07-30 08:31:23 | announced | |
⏵ 2 | 2024-10-22 06:51:48 | announced | 2024-10-22: Updated project metadata. |
Publication List
Keyword List
submitter keyword: Plasmodium, drug discovery, malaria, drug resistance, proteasome |
Contact List
Margaret A. Phillips |
contact affiliation | Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas 75390, USA |
contact email | margaret.phillips@utsouthwestern.edu |
lab head | |
Andrew Lemoff |
contact affiliation | UT Southwestern Medical Center |
contact email | andrew.lemoff@utsouthwestern.edu |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD052830
- Label: PRIDE project
- Name: Identification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria