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New 4-Aminoproline-Based Small Molecule Cyclopeptidomimetics as Potential Modulators of α4β1 Integrin.

Andrea SartoriKelly BugattiElisabetta PortioliMonica BaiulaIrene CasamassimaAgostino BrunoFrancesca BianchiniClaudio CurtiFranca ZanardiLucia Battistini
Published in: Molecules (Basel, Switzerland) (2021)
Integrin α4β1 belongs to the leukocyte integrin family and represents a therapeutic target of relevant interest given its primary role in mediating inflammation, autoimmune pathologies and cancer-related diseases. The focus of the present work is the design, synthesis and characterization of new peptidomimetic compounds that are potentially able to recognize α4β1 integrin and interfere with its function. To this aim, a collection of seven new cyclic peptidomimetics possessing both a 4-aminoproline (Amp) core scaffold grafted onto key α4β1-recognizing sequences and the (2-methylphenyl)ureido-phenylacetyl (MPUPA) appendage, was designed, with the support of molecular modeling studies. The new compounds were synthesized through SPPS procedures followed by in-solution cyclization maneuvers. The biological evaluation of the new cyclic ligands in cell adhesion assays on Jurkat cells revealed promising submicromolar agonist activity in one compound, namely, the c[Amp(MPUPA)Val-Asp-Leu] cyclopeptide. Further investigations will be necessary to complete the characterization of this class of compounds.
Keyphrases
  • cell adhesion
  • small molecule
  • protein kinase
  • induced apoptosis
  • oxidative stress
  • cell migration
  • cell cycle arrest
  • protein protein
  • high throughput
  • single cell
  • peripheral blood
  • cell death
  • drug induced