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Targeting NEDD9-SH3 with a Covalent Peptide Controls Endothelial Phenotype.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Src homology 3 (SH3) proteins are implicated in fibroproliferative diseases like pulmonary arterial hypertension (PAH).
  • Targeting SH3 proteins therapeutically presents significant challenges.
  • Neural precursor cell expressed, developmentally down-regulated 9 (NEDD9) is a pro-PAH regulator containing an SH3 domain.

Purpose of the Study:

  • To develop a novel peptidomimetic targeting the SH3 domain of NEDD9.
  • To investigate the therapeutic potential of NEDD9 inhibition in pulmonary arterial hypertension (PAH).
  • To elucidate the mechanisms by which NEDD9 influences endothelial cell phenotype and vascular remodeling.

Main Methods:

  • Design and synthesis of a bromoacetamide-derivatized peptidomimetic targeting NEDD9's FAK binding site.
  • Assessment of peptidomimetic effects on human pulmonary artery endothelial cell (HPAEC) migration and FAK binding.
  • Investigation of NEDD9 and sulfatase-1 (SULF1) interactions using siRNA and overexpression studies.
  • Evaluation of therapeutic efficacy in a rodent model of PAH.

Main Results:

  • The peptidomimetic covalently bound to NEDD9 (Cys18), inhibiting FAK binding and HPAEC migration.
  • NEDD9 inhibition, via siRNA or peptidomimetic, downregulated SULF1, promoting podosome formation and migration.
  • Sulfatase-1 knockdown prevented PAH-related vascular remodeling and reversed pulmonary hypertension in vivo.
  • The developed therapeutic approach demonstrated efficacy in reversing established PAH.

Conclusions:

  • A structure-validated covalent peptidomimetic targeting the NEDD9 SH3 domain was successfully developed.
  • NEDD9 regulates endothelial cell phenotype and vascular remodeling through convergent mechanisms involving sulfatase-1.
  • This study establishes a novel SH3-specific therapeutic strategy for PAH and other fibroproliferative disorders.