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

Andrea Sartori,Claudio Curti,Elisabetta Portioli,Irene Casamassima,Franca Zanardi,Monica Baiula,Agostino Bruno,Francesca Bianchini,Lucia Battistini,Kelly Bugatti

doi:10.3390/molecules26196066

Andrea Sartori, Claudio Curti + Show 8 more

Open Access

https://doi.org/10.3390/molecules26196066

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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 c[Amp(MPUPA)Val-Asp-Leu] cyclopeptide. Further investigations will be necessary to complete the characterization of this class of compounds.

Highlights

Integrins constitute a major class of cell adhesion receptors in mammals and play a vital role in cell–cell and cell–extracellular environment communication by regulating crucial aspects of cellular functions, including migration, adhesion, differentiation, growth, and survival
The α4β1 integrin, known as very late antigen-4 (VLA-4), raised much attention due to its being constitutively expressed on the surface of lymphocytes and most leukocytes, and being involved in coordinating leukocyte homing in various tissues [6]
We report the molecular modelling-driven design, the synthesis, and the chemical characterization of a collection of seven tetra- and pentacyclopeptidomimetics of type 7, as well as the evaluation of their binding competence towards the α4β1 integrin receptor by cell adhesion assays using Jurkat cells in the presence of vascular adhesion molecule-1 (VCAM-1), with the aim to preliminarily assess their ability to bind α4β1 integrin and possibly serve as modulators of integrin function

Summary

Introduction

Integrins constitute a major class of cell adhesion receptors in mammals and play a vital role in cell–cell and cell–extracellular environment communication by regulating crucial aspects of cellular functions, including migration, adhesion, differentiation, growth, and survival. They are expressed in almost all cell types with varied distribution pattern [1,2]. The integrin family comprises 24 different heterodimeric subtypes, classified according to the specific, non-covalent combination between α and β subunits. The α4β1 and α4β7 subtypes, as well as the β2 integrin subclass, belong to the leukocyte-specific integrin family and are involved in the modulation of immune functions. The α4β1 integrin, known as very late antigen-4 (VLA-4), raised much attention due to its being constitutively expressed on the surface of lymphocytes and most leukocytes, and being involved in coordinating leukocyte homing in various tissues [6]

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