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Phenelzine-based probes reveal Secernin-3 is involved in thermal nociception.
Bustin, Katelyn A; Shishikura, Kyosuke; Chen, Irene; Lin, Zongtao; McKnight, Nate; Chang, Yuxuan; Wang, Xie; Li, Jing Jing; Arellano, Eric; Pei, Liming; Morton, Paul D; Gregus, Ann M; Buczynski, Matthew W; Matthews, Megan L.
Afiliação
  • Bustin KA; Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Shishikura K; Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Chen I; School of Neuroscience, Virginia Polytechnic and State University, Blacksburg, VA 24061, USA.
  • Lin Z; Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • McKnight N; Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Chang Y; Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Wang X; Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Li JJ; Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • Arellano E; Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Pei L; Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • Morton PD; Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic and State University, Blacksburg, VA, 24060, USA.
  • Gregus AM; School of Neuroscience, Virginia Polytechnic and State University, Blacksburg, VA 24061, USA. Electronic address: agregus@vt.edu.
  • Buczynski MW; School of Neuroscience, Virginia Polytechnic and State University, Blacksburg, VA 24061, USA. Electronic address: mwb@vt.edu.
  • Matthews ML; Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: megamatt@sas.upenn.edu.
Mol Cell Neurosci ; 125: 103842, 2023 06.
Article em En | MEDLINE | ID: mdl-36924917
ABSTRACT
Chemical platforms that facilitate both the identification and elucidation of new areas for therapeutic development are necessary but lacking. Activity-based protein profiling (ABPP) leverages active site-directed chemical probes as target discovery tools that resolve activity from expression and immediately marry the targets identified with lead compounds for drug design. However, this approach has traditionally focused on predictable and intrinsic enzyme functionality. Here, we applied our activity-based proteomics discovery platform to map non-encoded and post-translationally acquired enzyme functionalities (e.g. cofactors) in vivo using chemical probes that exploit the nucleophilic hydrazine pharmacophores found in a classic antidepressant drug (e.g. phenelzine, Nardil®). We show the probes are in vivo active and can map proteome-wide tissue-specific target engagement of the drug. In addition to engaging targets (flavoenzymes monoamine oxidase A/B) that are associated with the known therapeutic mechanism as well as several other members of the flavoenzyme family, the probes captured the previously discovered N-terminal glyoxylyl (Glox) group of Secernin-3 (SCRN3) in vivo through a divergent mechanism, indicating this functional feature has biochemical activity in the brain. SCRN3 protein is ubiquitously expressed in the brain, yet gene expression is regulated by inflammatory stimuli. In an inflammatory pain mouse model, behavioral assessment of nociception showed Scrn3 male knockout mice selectively exhibited impaired thermal nociceptive sensitivity. Our study provides a guided workflow to entangle molecular (off)targets and pharmacological mechanisms for therapeutic development.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fenelzina / Nociceptividade Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fenelzina / Nociceptividade Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2023 Tipo de documento: Article