Druggability of CRMP2 for neurodegenerative diseases

Rajesh Khanna, Aubin Moutal, Samantha Perez-Miller, Aude Chefdeville, Lisa Boinon, Marcel Patek

Research output: Contribution to journalReview articlepeer-review

6 Scopus citations

Abstract

Collapsin response mediator proteins (CRMPs) are ubiquitously expressed phosphoproteins that coordinate cytoskeletal formation and regulate cellular division, migration, polarity, and synaptic connection. CRMP2, the most studied of the five family members, is best known for its affinity for tubulin heterodimers and function in regulating the microtubule network. Accumulating evidence has also demonstrated a key role for CRMP2 in trafficking of voltage- and ligand-gated ion channels. These functions are tightly regulated by post-translational modifications including phosphorylation and SUMOylation (addition of a small ubiquitin like modifier). Over the past decade, it has become increasingly clear that dysregulated post-translational modifications of CRMP2 contribute to the pathomechanisms of diverse diseases, including cancer, neurodegenerative diseases, chronic pain, and bipolar disorder. Here, we review the discovery, functions, and current putative preclinical and clinical therapeutics targeting CRMP2. These potential therapeutics include CRMP2-based peptides that inhibit protein-protein interactions and small-molecule compounds. Capitalizing on the availability of structural information, we identify druggable pockets on CRMP2 and predict binding modes for five known CRMP2-targeting compounds, setting the stage for optimization and de novo drug discovery targeting this multifunctional protein.

Original languageEnglish (US)
Pages (from-to)2492-2505
Number of pages14
JournalACS Chemical Neuroscience
Volume11
Issue number17
DOIs
StatePublished - Sep 2 2020

Keywords

  • CBD3 peptide
  • CRMP2
  • edonerpic maleate
  • lacosamide
  • lanthionine ketimine ester
  • naringenin

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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