Affinity‐Based Chemoproteomics for Target Identification

Jensen, Annika Jenmalm; Cornella-Taracido, Ivan

doi:10.1002/9783527818242.ch2

Cited by 5 publications

(4 citation statements)

References 65 publications

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“…We therefore sought to exploit the electrophilic nature of PCB to elucidate its protein binding partners though affinity capture [32,33] . A chemical proteomics approach to target identification was thus envisioned using PCB‐based probes bearing a click handle for subsequent ligation to a detection or enrichment handle (e. g., a fluorophore or biotin) to enable identification of protein binding partners by LC–MS/MS analysis (Figure 4A).…”

Section: Resultsmentioning

confidence: 99%

The Cyanobacterial “Nutraceutical” Phycocyanobilin Inhibits Cysteine Protease Legumain

et al. 2023

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The blue biliprotein phycocyanin, produced by photo-autotrophic cyanobacteria including spirulina (Arthrospira) and marketed as a natural food supplement or "nutraceutical," is reported to have anti-inflammatory, antioxidant, immunomodulatory, and anticancer activity. These diverse biological activities have been specifically attributed to the phycocyanin chromophore, phycocyanobilin (PCB). However, the mechanism of action of PCB and the molecular targets responsible for the beneficial properties of PCB are not well understood. We have developed a procedure to rapidly cleave the PCB pigment from phycocyanin by ethanolysis and then characterized it as an electrophilic natural product that interacts covalently with thiol nucleophiles but lacks any appreciable cytotoxicity or antibacterial activity against common pathogens and gut microbes. We then designed alkyne-bearing PCB probes for use in chemical proteomics target deconvolution studies. Target identification and validation revealed the cysteine protease legumain (also known as asparaginyl endopeptidase, AEP) to be a target of PCB. Inhibition of this target may account for PCB's diverse reported biological activities.

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Section: Resultsmentioning

confidence: 99%

The Cyanobacterial “Nutraceutical” Phycocyanobilin Inhibits Cysteine Protease Legumain

et al. 2023

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“…These approaches can be used to identify interactions characterized by non-covalent and coordinative bonds. Covalent capture of drug-target interaction in cells can be used to identify physiological-occurring and moderately strong binding events by affinity-based chemoproteomics in vivo [55,56].…”

Section: Figurementioning

confidence: 99%

From the Discovery of Targets to Delivery Systems: How to Decipher and Improve the Metallodrugs Actions at Molecular Level

Iacobucci,

La Manna,

Cipollone

et al. 2023

Preprint

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Metals are indispensable in the life of all organisms, in fact, their dysregulation causes various disorders caused by an interruption of their homeostasis. Nowadays different transition metals are incorporated into pharmaceutical products as diagnostic and therapeutic agents because of their electronic structure which gives them versatility in terms of tuning molecule properties, differently from organic molecules. Hence the interest in the study of metal-drug complexes from different points of view was born and many approaches were developed for the characterization, activation, delivery and molecular mechanisms clarification. The integration of these different approaches starting from chemoproteomics passing through nanoparticle systems to different activation strategies allows the understanding of the cellular responses of metallic drugs, which can be the basis for the design of new drugs and/or modification of drugs currently in use. This review aims to briefly summarize the recent advances in this area by describing the technological platforms and their possible applications to identify protein targets for discovering the mechanisms of action of metallodrugs, and to improve their efficiency in terms of administration.

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“…Therefore. functionalized analogues, entailing an affinity tag, allow target enrichment within a complex protein mixture [40]. In order to design a bioactive functionalized pakerine analogue, we first assessed which functional groups are required for the stress-alleviating effects of pakerine through a SAR analysis.…”

Section: Structure-activity Relationship (Sar) Analysis Of Pakerinementioning

confidence: 99%

Chemical Genetics Approach Identifies Abnormal Inflorescence Meristem 1 as a Putative Target of a Novel Sulfonamide That Protects Catalase2-Deficient Arabidopsis against Photorespiratory Stress

Meer

Verlee

Willems

et al. 2020

Cells

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Alterations of hydrogen peroxide (H2O2) levels have a profound impact on numerous signaling cascades orchestrating plant growth, development, and stress signaling, including programmed cell death. To expand the repertoire of known molecular mechanisms implicated in H2O2 signaling, we performed a forward chemical screen to identify small molecules that could alleviate the photorespiratory-induced cell death phenotype of Arabidopsisthaliana mutants lacking H2O2-scavenging capacity by peroxisomal catalase2. Here, we report the characterization of pakerine, an m-sulfamoyl benzamide from the sulfonamide family. Pakerine alleviates the cell death phenotype of cat2 mutants exposed to photorespiration-promoting conditions and delays dark-induced senescence in wild-type Arabidopsis leaves. By using a combination of transcriptomics, metabolomics, and affinity purification, we identified abnormal inflorescence meristem 1 (AIM1) as a putative protein target of pakerine. AIM1 is a 3-hydroxyacyl-CoA dehydrogenase involved in fatty acid β-oxidation that contributes to jasmonic acid (JA) and salicylic acid (SA) biosynthesis. Whereas intact JA biosynthesis was not required for pakerine bioactivity, our results point toward a role for β-oxidation-dependent SA production in the execution of H2O2-mediated cell death.

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Affinity‐Based Chemoproteomics for Target Identification

Cited by 5 publications

References 65 publications

The Cyanobacterial “Nutraceutical” Phycocyanobilin Inhibits Cysteine Protease Legumain

The Cyanobacterial “Nutraceutical” Phycocyanobilin Inhibits Cysteine Protease Legumain

From the Discovery of Targets to Delivery Systems: How to Decipher and Improve the Metallodrugs Actions at Molecular Level

Chemical Genetics Approach Identifies Abnormal Inflorescence Meristem 1 as a Putative Target of a Novel Sulfonamide That Protects Catalase2-Deficient Arabidopsis against Photorespiratory Stress

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