ArticleMalaria journal2015
Inhibition by stabilization: targeting the Plasmodium falciparum aldolase-TRAP complex.
Article in Malaria journal, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 27 citations in OpenAlex.
- Induced proximity-based therapeutic modalities.Nature reviews. Drug discovery · 2026Review
- SE(3)-equivariant ternary complex prediction towards target protein degradation.Nature communications · 2025Article
- Exploring Biomarkers for Malaria: Advances in Early Detection and Asymptomatic Diagnosis.Biosensors · 2025Review
- Novel quinolinepiperazinyl-aryltetrazoles targeting the blood stage ofRSC medicinal chemistry · 2024Article
- Molecular Glue Discovery: Current and Future Approaches.Journal of medicinal chemistry · 2023Review
- Thrombospondin Related Anonymous Protein Superfamily in Vector-Borne Apicomplexans: The Parasite's Toolkit for Cell Invasion.Frontiers in cellular and infection microbiology · 2022Review
- A System for the Evolution of Protein-Protein Interaction Inducers.ACS synthetic biology · 2021Article
- In silico identification of novel open reading frames in Plasmodium falciparum oocyte and salivary gland sporozoites using proteogenomics framework.Malaria journal · 2021Article
- Multifunctional Fructose 1,6-Bisphosphate Aldolase as a Therapeutic Target.Frontiers in molecular biosciences · 2021Review
- Multiplexed quantitative proteomics provides mechanistic cues for malaria severity and complexity.Communications biology · 2020Article
- Identification and molecular characterization of a novel Babesia orientalis thrombospondin-related anonymous protein (BoTRAP1).Parasites & vectors · 2018Article
- Discovery of Plasmodium (M)TRAP-Aldolase Interaction Stabilizers Interfering with Sporozoite Motility and Invasion.ACS infectious diseases · 2018Article
- A Putative Small Solute Transporter Is Responsible for the Secretion of G377 and TRAP-Containing Secretory Vesicles during Plasmodium Gamete Egress and Sporozoite Motility.PLoS pathogens · 2016Article
- The Binding of Plasmodium falciparum Adhesins and Erythrocyte Invasion Proteins to Aldolase Is Enhanced by Phosphorylation.PloS one · 2016Article
Corrections and comments
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Authors and funding
12 authors at 6 institutions in 4 countries.
Funding
Abstract
backgroundEmerging resistance of the malaria parasite Plasmodium to current therapies underscores the critical importance of exploring novel strategies for disease eradication. Plasmodium species are obligate intracellular protozoan parasites. They rely on an unusual form of substrate-dependent motility for their migration on and across host-cell membranes and for host cell invasion. This peculiar motility mechanism is driven by the 'glideosome', an actin-myosin associated, macromolecular complex anchored to the inner membrane complex of the parasite. Myosin A, actin, aldolase, and thrombospondin-related anonymous protein (TRAP) constitute the molecular core of the glideosome in the sporozoite, the mosquito stage that brings the infection into mammals.
methodsVirtual library screening of a large compound library against the PfAldolase-TRAP complex was used to identify candidate compounds that stabilize and prevent the disassembly of the glideosome. The mechanism of these compounds was confirmed by biochemical, biophysical and parasitological methods.
resultsA novel inhibitory effect on the parasite was achieved by stabilizing a protein-protein interaction within the glideosome components. Compound 24 disrupts the gliding and invasive capabilities of Plasmodium parasites in in vitro parasite assays. A high-resolution, ternary X-ray crystal structure of PfAldolase-TRAP in complex with compound 24 confirms the mode of interaction and serves as a platform for future ligand optimization.
conclusionThis proof-of-concept study presents a novel approach to anti-malarial drug discovery and design. By strengthening a protein-protein interaction within the parasite, an avenue towards inhibiting a previously "undruggable" target is revealed and the motility motor responsible for successful invasion of host cells is rendered inactive. This study provides new insights into the malaria parasite cell invasion machinery and convincingly demonstrates that liver cell invasion is dramatically reduced by 95 % in the presence of the small molecule stabilizer compound 24.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.