Publications by authors named "L K Kirkman"
We report two cases of recurrent malaria in U.S. travelers returning from Africa (Ghana and Central African Republic) despite a full course of artemether-lumefantrine (AL).
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- Artezomibs (ATZs) are innovative molecules that combine artemisinin with a proteasome inhibitor, targeting the malaria parasite's proteasome system.
- The study outlines a detailed protocol for using a fluorescent probe to investigate how ATZs transform into effective proteasome inhibitors inside malaria parasites.
- Key steps in the protocol involve drug treatment, washing out the drug, lysing the parasites, labeling the proteasome, and visualizing the results.
Article Synopsis
- * A new macrocyclic peptide, TDI-8304, has been created, showing strong selectivity for the parasite's proteasome over humans and effective results in lab and live tests against P. falciparum.
- * Research reveals that mutations in the Pf20S proteasome can lead to drug resistance, but also create opportunities for designing more effective inhibitors by understanding how these mutations impact drug binding and efficacy.*
Artemisinins (ART) are critical anti-malarials and despite their use in combination therapy, ART-resistant Plasmodium falciparum is spreading globally. To counter ART resistance, we designed artezomibs (ATZs), molecules that link an ART with a proteasome inhibitor (PI) via a non-labile amide bond and hijack parasite's own ubiquitin-proteasome system to create novel anti-malarials in situ. Upon activation of the ART moiety, ATZs covalently attach to and damage multiple parasite proteins, marking them for proteasomal degradation.
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- The proteasome of the Plasmodium falciparum parasite is a valuable target for developing new antimalarial treatments, as certain inhibitors can effectively work alongside artemisinin drugs, even against drug-resistant strains.
- Among the inhibitors studied, vinyl sulfones showed strong effectiveness against resistant parasites and did not promote further resistance, with one variant demonstrating permanent binding to key proteasome components.
- Additionally, alternative resistance mechanisms could lead to increased sensitivity to different types of inhibitors, and using genetic editing methods, researchers confirmed how changes in the proteasome structure affect drug binding, highlighting the potential for dual-targeting strategies in malaria treatment.