Dehydro-β-proline Containing α4β1 Integrin Antagonists: Stereochemical Recognition in Ligand-Receptor Interplay.

A novel class of dehydro-β-proline-containing peptidomimetics, designed to be effective as α4β1 integrin ligands, has been developed on the basis of the fundamental requirements for the interactions of these transmembrane receptors with bioactive ligands. Dehydro-β-proline ring has been synthesized through an original pathway, involving ring closing metathesis of a diallylamino derivative. The synthesized products showed to be effective and selective as α4β1 integrin antagonists and displayed IC50 values in the nanomolar range in cell adhesion inhibition assays and in VCAM-1-induced phosphorylation of extracellular-signal-regulated kinases. Significant activity was observed also toward the homologous integrin α4β7, while they did not display any activity toward selected members of β1, β2, and β3 families. A strong dependence on the stereochemistry of the heterocyclic central core could be observed. The great importance of α4β1 integrin in chronic inflammatory and autoimmune diseases suggests a possible exploitation of these ligands as lead compounds for therapeutic tools development.

[1]  G. Hajishengallis,et al.  Leukocyte integrins: role in leukocyte recruitment and as therapeutic targets in inflammatory disease. , 2015, Pharmacology & therapeutics.

[2]  Karly P Garnock-jones,et al.  Vedolizumab: A Review of Its Use in Adult Patients with Moderately to Severely Active Ulcerative Colitis or Crohn’s Disease , 2014, BioDrugs.

[3]  G. Lizée,et al.  B-Raf Regulation of Integrin α4β1-mediated Resistance to Shear Stress through Changes in Cell Spreading and Cytoskeletal Association in T Cells* , 2014, The Journal of Biological Chemistry.

[4]  H. Bönig,et al.  Role of Integrin Alpha4 in Drug Resistance of Leukemia , 2014, Front. Oncol..

[5]  L. Gentilucci,et al.  Synthesis and assay of retro-α4β1 integrin-targeting motifs. , 2014, European journal of medicinal chemistry.

[6]  F. Vidal-Vanaclocha,et al.  IL-18 regulates melanoma VLA-4 integrin activation through a Hierarchized sequence of inflammatory factors. , 2014, The Journal of investigative dermatology.

[7]  T. Hellevik,et al.  Radiotherapy and the Tumor Stroma: The Importance of Dose and Fractionation , 2014, Front. Oncol..

[8]  P. L. McCormack.  Natalizumab: A Review of Its Use in the Management of Relapsing-Remitting Multiple Sclerosis , 2013, Drugs.

[9]  Zhenmei Liao,et al.  Orally available and efficacious α4β1/α4β7 integrin inhibitors. , 2013, Bioorganic & medicinal chemistry letters.

[10]  R. Dixon,et al.  Small Molecule Agonist of Very Late Antigen-4 (VLA-4) Integrin Induces Progenitor Cell Adhesion* , 2013, The Journal of Biological Chemistry.

[11]  C. M. Carlevaro,et al.  PLAUSIBLE BINDING MODE OF THE ACTIVE α4β1 ANTAGONIST, MK-0617, DETERMINED BY DOCKING AND FREE ENERGY CALCULATIONS , 2013 .

[12]  A. Ray,et al.  Synthesis and evaluation of 4,5-dihydro-5-methylisoxazolin-5-carboxamide derivatives as VLA-4 antagonists. , 2013, Bioorganic & medicinal chemistry letters.

[13]  D. Rubin,et al.  Natalizumab in Crohn’s Disease: Results From a US Tertiary Inflammatory Bowel Disease Center , 2013, Inflammatory bowel diseases.

[14]  O. Feron,et al.  Diaryl urea LDV peptidomimetics as α4β1 integrin antagonists: synthesis, adhesion inhibition and toxicity evaluation on CCRF-CEM cell line , 2012 .

[15]  J. Chiba,et al.  Identification of trans-4-[1-[[7-fluoro-2-(1-methyl-3-indolyl)-6-benzoxazolyl]acetyl]-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid as a potent, orally active VLA-4 antagonist. , 2012, Bioorganic & medicinal chemistry.

[16]  Oliver E. Hutt,et al.  Modeling the molecular basis for α4β1 integrin antagonism. , 2011, Bioorganic & medicinal chemistry.

[17]  S. Sakkiah,et al.  Discovery of Potential Integrin VLA‐4 Antagonists Using Pharmacophore Modeling, Virtual Screening and Molecular Docking Studies , 2011, Chemical biology & drug design.

[18]  L. Gentilucci,et al.  A straightforward route to enantiopure 2-substituted-3,4-dehydro-β-proline via ring closing metathesis , 2011, Amino Acids.

[19]  Minsoo Kim,et al.  Leukocyte integrins and their ligand interactions , 2009, Immunologic research.

[20]  P. Govoni,et al.  Contribution of alpha4beta1 integrin to the antiallergic effect of levocabastine. , 2008, Biochemical pharmacology.

[21]  D. Stupack,et al.  A homing mechanism for bone marrow-derived progenitor cell recruitment to the neovasculature. , 2006, The Journal of clinical investigation.

[22]  K. Tyler,et al.  Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. , 2005, The New England journal of medicine.

[23]  R. Hwang,et al.  Integrin α4β1–VCAM-1–mediated adhesion between endothelial and mural cells is required for blood vessel maturation , 2005 .

[24]  D. Huryn,et al.  The identification and optimization of orally efficacious, small molecule VLA-4 antagonists. , 2004, Current topics in medicinal chemistry.

[25]  W. Hagmann.  The discovery and potential of N-sulfonylated dipeptide VLA-4 antagonists. , 2004, Current topics in medicinal chemistry.

[26]  N. Fotouhi,et al.  The discovery of VLA-4 antagonists. , 2004, Current topics in medicinal chemistry.

[27]  H. Kessler,et al.  Synthesis and Structure−Activity Relationship of Mannose-Based Peptidomimetics Selectively Blocking Integrin α4β7 Binding to Mucosal Addressin Cell Adhesion Molecule-1 , 2003 .

[28]  G. Müller,et al.  Medicinal chemistry of target family-directed masterkeys. , 2003, Drug discovery today.

[29]  J. Nicholas,et al.  Solid-phase synthesis of dual α4β1/α4β7 integrin antagonists: two scaffolds with overlapping pharmacophores , 2002 .

[30]  Richard O Hynes,et al.  Integrins Bidirectional, Allosteric Signaling Machines , 2002, Cell.

[31]  D. Sutherlin,et al.  Selective α4β7 Integrin Antagonists and Their Potential as Antiinflammatory Agents , 2002 .

[32]  Herman W. T. van Vlijmen,et al.  Identification of Potent and Novel α4β1 Antagonists Using in Silico Screening , 2002 .

[33]  David Y Jackson,et al.  Alpha 4 integrin antagonists. , 2002, Current pharmaceutical design.

[34]  David A. Cheresh,et al.  Role of integrins in cell invasion and migration , 2002, Nature Reviews Cancer.

[35]  W. DeGrado,et al.  β-Peptides: From Structure to Function , 2001 .

[36]  W. DeGrado,et al.  beta-Peptides: from structure to function. , 2001, Chemical reviews.

[37]  H. Kessler,et al.  Design and Synthesis of Potent and Selective a 4 7 Integrin Antagonists , 2001 .

[38]  R. B. Pepinsky,et al.  Selective, tight-binding inhibitors of integrin α4β1 that inhibit allergic airway responses , 1999 .

[39]  S. Deventer,et al.  Altered expression of alpha 4 beta 7, a gut homing integrin, by circulating and mucosal T cells in colonic mucosal inflammation. , 1997, Gut.

[40]  W. C. Still,et al.  Molecular Mechanics Parameters and Conformational Free Energies of Proline-Containing Peptides , 1996 .

[41]  D. I. Stuart,et al.  Crystal structure of an integrin-binding fragment of vascular cell adhesion molecule-1 at 1.8 Å resolution , 1995, Nature.

[42]  F. Sánchez‐Madrid,et al.  Alpha 4 beta 7 integrin mediates B cell binding to fibronectin and vascular cell adhesion molecule-1. Expression and function of alpha 4 integrins on human B lymphocytes. , 1993, Journal of immunology.

[43]  E. Berg,et al.  α4β7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1 , 1993, Cell.

[44]  M. Humphries,et al.  The CS5 peptide is a second site in the IIICS region of fibronectin recognized by the integrin alpha 4 beta 1. Inhibition of alpha 4 beta 1 function by RGD peptide homologues. , 1991, The Journal of biological chemistry.

[45]  I. M. Neiman,et al.  [Inflammation and cancer]. , 1974, Patologicheskaia fiziologiia i eksperimental'naia terapiia.

[46]  L. Dardenne,et al.  Analysis of α4 β1integrin specific antagonists binding modes: structural insights by molecular docking, molecular dynamics and linear interaction energy method for free energy calculations , 2010 .

[47]  L. Dardenne,et al.  Analysis of α 4 β 1 Integrin Specific Antagonists Binding Modes : Structural Insights by Molecular Docking , Molecular Dynamics and Linear Interaction Energy Method for Free Energy Calculations , 2010 .

[48]  Y. Kang,et al.  Conformational preferences and cis–trans isomerization of L‐3,4‐dehydroproline residue , 2009, Biopolymers.

[49]  Jian Li,et al.  A 3D Structure Model of Integrin α4β1 Complex: I. Construction of a Homology Model of β1 and Ligand Binding Analysis , 2002 .

[50]  F. Sánchez‐Madrid,et al.  The α4β1/VCAM-1 adhesion pathway in physiology and disease , 1993 .

[51]  Kenneth,et al.  The CS 5 Peptide Is a Second Site in the IIICS Region of Fibronectin Recognized by the Integrin , 2022 .

[52]  Deventer,et al.  Altered expression of Oc4 ,7 a gut homing integrin, by circulating and mucosal T cells in colonic mucosal inflammation , 2022 .