Activity‐Based Protein Profiling of Oxidases and Reductases

Krammer, Leo; Breinbauer, Rolf

doi:10.1002/ijch.202200086

Cited by 3 publications

(2 citation statements)

References 86 publications

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“…So far, very few oxidoreductases have been identified as antimalarial drug targets. [13,14] In the last decade, we have discovered an early lead redoxactive compound, called plasmodione (PD), belonging to the 3benzylmenadione (benzylMD) family, with a unique mechanism of action [15] that has been partly deciphered (Figure 1, panel A). PD acts as a prodrug entering in a cascade of redox reactions, with highest activity in young early stages and gametocytes.…”

Section: Introductionmentioning

confidence: 99%

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Proteomic Profiling of Antimalarial Plasmodione Using 3‐Benz(o)ylmenadione Affinity‐Based Probes

Iacobucci,

Monaco,

Hovasse

et al. 2024

ChemBioChem

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Understanding the mechanisms of drug action in malarial parasites is crucial for the development of new drugs to combat infection and to counteract drug resistance. Proteomics is a widely used approach to study host‐pathogen systems and to identify drug protein targets. Plasmodione is an antiplasmodial early‐lead drug exerting potent activities against young asexual and sexual blood stages in vitro with low toxicity to host cells. To elucidate its molecular mechanisms, an affinity‐based protein profiling (AfBPP) approach was applied to yeast and P. falciparum proteomes. New (pro‐)AfBPP probes based on the 3‐benz(o)yl‐6‐fluoro‐menadione scaffold were synthesized. With optimized conditions of both photoaffinity labeling and click reaction steps, the AfBPP protocol was then applied to a yeast proteome, yielding 11 putative drug‐protein targets. Among these, we found four proteins associated with oxidoreductase activities, the hypothesized type of targets for plasmodione and its metabolites, and other proteins associated with the mitochondria. In Plasmodium parasites, the MS analysis revealed 44 potential plasmodione targets that need to be validated in further studies. Finally, the localization of a 3‐benzyl‐6‐fluoromenadione AfBPP probe was studied in the subcellular structures of the parasite at the trophozoite stage.

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Section: Introductionmentioning

confidence: 99%

“…Open access to the full Plasmodium genome and proteome has brought new opportunities to identify novel drug targets. So far, very few oxidoreductases have been identified as antimalarial drug targets [13,14] …”

Section: Introductionmentioning

confidence: 99%

Proteomic Profiling of Antimalarial Plasmodione Using 3‐Benz(o)ylmenadione Affinity‐Based Probes

Iacobucci,

Monaco,

Hovasse

et al. 2024

ChemBioChem

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Covalent Modification of Protein by Chemical Probe in Living Cells for Structural and Interaction Studies

Zheng,

Cheng,

et al. 2024

ChemBioChem

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Cellular activities are predominantly carried out by proteins that can dynamically adopt different structural conformations and differentially interact with other biomolecules according to cellular needs. Chemical probes are small molecules used to selectively interact and modulate the activities of specific proteins to study their functions such as the validation of potential drug targets. The remarkable performance of AlphaFold algorithms in the prediction of protein structures has pivoted interest toward elucidating the intracellular dynamics of protein structural conformation where covalent modification of proteins by chemical probes could be used to shed light upon. However, due to the barrier to entry by cell membrane and the general unfavorable reactive conditions of the intracellular environment, most studies using reactive chemical probes are still conducted on purified proteins and cell lysates. Nevertheless, recent progresses have been made in designing chemical probes with improved membrane permeability, stability and reactivity. This paper surveys the literature on recent advancements in membrane‐permeable chemical probes and their applications with protein mass spectrometry for the intracellular studies of protein structural conformations and biomolecular interactions.

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Activity-based protein profiling in drug/pesticide discovery: Recent advances in target identification of antibacterial compounds

Chen,

Zhang,

Ding

et al. 2024

Bioorganic Chemistry

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Activity‐Based Protein Profiling of Oxidases and Reductases

Abstract: Dedicated to Prof. Benjamin Cravatt on the occasion of being awarded the Wolf Prize in Chemistry.

Cited by 3 publications

References 86 publications

Proteomic Profiling of Antimalarial Plasmodione Using 3‐Benz(o)ylmenadione Affinity‐Based Probes

Proteomic Profiling of Antimalarial Plasmodione Using 3‐Benz(o)ylmenadione Affinity‐Based Probes

Covalent Modification of Protein by Chemical Probe in Living Cells for Structural and Interaction Studies

Activity-based protein profiling in drug/pesticide discovery: Recent advances in target identification of antibacterial compounds

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