New 4-Aminoproline-Based Small Molecule Cyclopeptidomimetics as Potential Modulators of α4β1 Integrin |
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| Authors: | Andrea Sartori Kelly Bugatti Elisabetta Portioli Monica Baiula Irene Casamassima Agostino Bruno Francesca Bianchini Claudio Curti Franca Zanardi Lucia Battistini |
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| Institution: | 1.Department of Food and Drug, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy; (A.S.); (K.B.); (E.P.); (A.B.); (C.C.); (F.Z.);2.Department of Pharmacy and Biotechnology, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy; (M.B.); (I.C.);3.Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale G.B. Morgagni 50, 50134 Firenze, Italy; |
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| Abstract: | 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 cAmp(MPUPA)Val-Asp-Leu] cyclopeptide. Further investigations will be necessary to complete the characterization of this class of compounds. |
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| Keywords: | aminoproline scaffold integrin targeting ligand design peptidomimetic synthesis leukocyte integrins |
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