2. Academic Validation
  3. RAGE-mediated activation of the formin DIAPH1 and human macrophage inflammation are inhibited by a small molecule antagonist

RAGE-mediated activation of the formin DIAPH1 and human macrophage inflammation are inhibited by a small molecule antagonist

  • Cell Chem Biol. 2025 Oct 16;32(10):1221-1234.e8. doi: 10.1016/j.chembiol.2025.09.004.
Gregory G Theophall 1,  Michaele B Manigrasso 2,  Parastou Nazarian 1,  Aaron Premo 1,  Sergey Reverdatto 1,  Gautham Yepuri 2,  David S Burz 1,  Sally M Vanegas 3,  Kaamashri Mangar 2,  Yanan Zhao 4,  Huilin Li 4,  Robert J DeVita 5,  Ravichandran Ramasamy 2,  Ann Marie Schmidt 6,  Alexander Shekhtman 7
Affiliations

Affiliations

  • 1 Department of Chemistry, State University of New York at Albany, Albany, NY 12222, USA.
  • 2 Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 3 Department of Medicine, New York Grossman School of Medicine, New York, NY 10016, USA.
  • 4 Division of Biostatistics, Department of Population Health, New York University School of Medicine, New York, NY 10016, USA.
  • 5 RJD Medicinal Chemistry and Drug Discovery Consulting LLC, Westfield, NJ 07091, USA.
  • 6 Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA. Electronic address: annmarie.schmidt@nyulangone.org.
  • 7 Department of Chemistry, State University of New York at Albany, Albany, NY 12222, USA. Electronic address: ashekhtman@albany.edu.
PMID: 41038162 DOI: 10.1016/j.chembiol.2025.09.004
Abstract

RAGE and its intracellular effector molecule, the actin polymerase DIAPH1, mediate inflammation and the complications of diabetes. Using NMR spectroscopy and mass spectrometry, we built a structural model of the RAGE-DIAPH1 complex, revealing how binding of the cytoplasmic tail of RAGE (ctRAGE) to DIAPH1 stimulates its actin polymerization activity, which is inhibited by a small molecule antagonist of RAGE-DIAPH1 interaction, RAGE406R. The solution structure of the RAGE406R - ctRAGE suggests that RAGE406R prevents the formation of the RAGE-DIAPH1. FRET, actin polymerization assays, smooth muscle cell migration, and THP1 cell inflammation experiments, together with the in vivo interrogation of the effects of RAGE406R in mouse models of inflammation and diabetic wound healing, support this mode of RAGE-DIAPH1 antagonism. Finally, the treatment of macrophages differentiated from peripheral blood-derived mononuclear cells from humans with type 1 diabetes with RAGE406R reduces the mRNA expression of the chemokine CCL2, diminishing the expression of a key node in the inflammatory response.

Keywords

DIAPH1; NMR; actin polymerization; cross-linking; diabetes; intrinsically disordered regions; mDia1; mass spectrometry; protein-protein interactions; receptor for advanced glycation end products.

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