Baiula M.

De Marco R.

Dehshahri A.

Dodero V. I.

English

Archivio istituzionale della ricerca - Alma Mater Studiorum Università di Bologna

Editorial: Integrin Ligands and TheirBioconjugate Systems: Synthesis,Conformation, and Biological ActivityRossella De Marco1*, Ali Dehshahri 2, Monica Baiula3 and Veronica I. Dodero41Organic Chemistry, Department of Agricultural, Food, Environmental and Animal Sciences (Di4A), University of Udine, Udine,Italy, 2Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran,3Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy, 4Organic, Biomolecular and TranslationalChemistry, Department of Chemistry, University of Bielefeld, Bielefeld, GermanyKeywords: heterocycles, peptidomimetics, antagonists, nanoparticles, integrin, ligands, SAREditorial on the Research TopicIntegrin Ligands and their Bioconjugate Systems: Synthesis, Conformation, and BiologicalActivityIntegrins are one of the most important families of cell adhesion receptors that mediate cell-cell andcell-extracellular matrix interactions. These receptors are involved in tissue integrity and celltrafficking, growth, differentiation, proliferation, migration, and signal transduction. Integrinsare also involved in pathological processes such as inflammation, wound healing, angiogenesis,and tumor metastasis. Therefore, pharmacological inhibition of integrins is of great interest for thetreatment and prevention of diseases. The synthesis of antagonists capable of blocking the interactionof integrin with their cell adhesion molecule (CAM) or extra cellular matrix (ECM) ligands mayrepresent a promising approach to treat various pathological conditions.Integrin ligands, such as RDG, LDV, or BIO1211 show high activity in vitro but rapid enzymatichydrolysis and clearance in vivo. Mimetics with unnatural amino acids or heterocycles and smallmolecule moieties have been developed in order to increase the metabolic stability of the ligands. Amajor unresolved issue in the development of new integrin-antagonists is their low level of activitycompared to the precursor (e.g.: RGD or BIO1211). In this issue, a series of promising approaches forthe conjugation of integrin ligands and their biological applications have been described.Paulus and Sewald prepared a linear RGD mimetic containing small molecule-drug conjugate(SMDC). To prepare these mimetics the authors used an interesting approach namely the dualactivity-difference (DAD) mapping, a methodology to visualize activity/selectivity changes againsttwo different receptors upon partial structural changes in an array of molecules. They synthesized anRGD linear peptide and linked it by click-chemistry with an antimitotic agent monomethylauristatinE (MMAE) as SMDC. In parallel, the authors prepared cRGDfK-SMDC as a positive control, andcRADfK-SMDC as a negative control. The activity was tested by cell adhesion assay and the resultsshowed that the RGD- and cRGDfK-SMDC displayed a micromolar potency to inhibit αvβ3 integrin-mediated cell adhesion compared to the negative control which showed no effect.As a different strategy, integrin ligands can also be exploited as targeting moieties, binding tooverexpressed integrins on cancer cells in order to selectively deliver cytotoxic drugs. Schneider et al.described the development and evaluation of a promising targeted antitumor strategy. They used ascaffold composed of a human Fc functionalized by dextran, RGD ligands, and the cytotoxic drugMMAE. The Fc fragment was the centerpiece of the structure and was conjugated with both MMAE,through a self-immolative linker, and dextran, which allowed the multimeric presentation of RGDligands. It was demonstrated that the Fc-dextran RGD-decorated scaffold was able to specificallyEdited and reviewed by:Michael Kassiou,The University of Sydney, Australia*Correspondence:Rossella De Marcorossella.demarco@uniud.itSpecialty section:This article was submitted toMedicinal and PharmaceuticalChemistry,a section of the journalFrontiers in ChemistryReceived: 27 May 2022Accepted: 31 May 2022Published: 16 June 2022Citation:De Marco R, Dehshahri A, Baiula Mand Dodero VI (2022) Editorial: IntegrinLigands and Their BioconjugateSystems: Synthesis, Conformation,and Biological Activity.Front. Chem. 10:954618.doi: 10.3389/fchem.2022.954618Frontiers in Chemistry | www.frontiersin.org June 2022 | Volume 10 | Article 9546181EDITORIALpublished: 16 June 2022doi: 10.3389/fchem.2022.954618bind to cancer cells endogenously expressing αvβ3 integrin, ifcompared to a RAD-decorated scaffold, considered as a negativecontrol. Moreover, RGD-decorated construct showed an anti-proliferative effect in cancer cells in vitro, suggesting integrin-mediated endocytosis, followed by endosomal cleavage of theMMAE linker and its subsequent release within cancer cellsexpressing αvβ3 integrin.Conjugation of integrin ligands to NPs represents an effectiveapproach to address the intrinsic drawbacks of the nativepeptides, providing access to a variety of biomedical uses suchas nano-carriers and drug delivery systems. Sacchi et al. exploredthis last approach. They used gold nanoparticles functionalizedwith cyclized CGisoDGRG peptide (iso1), which contains theisoDGR sequence to recognize αvβ3 integrin receptor in cancercells. Iso1 was coupled via its thiol group to maleimide-PEG11-lipoamide (LPA) to obtain nanogold-iso1-PEG11-LPA.Nanogold-iso1 can be functionalized also with bioactive tumornecrosis factor-α (TNF-α) and it can be stored for days or forlonger than 1 year at low temperature without losing thecapability to bind αvβ3 integrin and TNF-α-mediated cytotoxicactivity. In in vitro experiment, nanogold-iso1-PEG11-LPAdemonstrated the ability to bind purified αvβ3 and to αvβ3-expressing cells. The activity of nanogold linked with both iso1and TNF-α was higher in removing the tumor in WEHI-164fibrosarcoma-bearing mice than nanoparticles lacking cyclizedCGisoDGRG peptide.Besides targeted drug delivery, integrin ligands-conjugatedmolecules can also be used for tumor imaging. Thebiodistribution of imaging probes in vivo depends both ontheir chemical structure and their pharmacokinetic properties.The latter can be altered using different strategies, including theexploitation of serum albumin as a transporter. Holtke et al.described the modification of a previously developed fluorescentRGD mimetic probe with three different albumin bindingmoieties (ABMs), with the aim of improving itspharmacokinetic properties. In particular, αvβ3-targetedfluorescent RGD mimetics biodistribution and tumor targetingabilities were analyzed for 1 week in a murine U87MGglioblastoma xenograft model. The results of the study showedthat RGD mimetics modified with ABMs accumulated in tumortissue for at least 5 days as compared to the unmodified probe,which was rapidly excreted. Moreover, the three ABM-modifiedprobes displayed different biodistribution and excretionproperties, thus allowing a fine-tuning of ABM modified RGDmimetics’ pharmacokinetic properties.With this special issue, we collected some studies on newintegrin ligands and their conjugated forms, and explored recentapplications to help the development of new therapeuticstrategies for diseases such as cancer.AUTHOR CONTRIBUTIONSConceptualization, RDM; writing-original draft, RDM and MB;writing-review and editing, RDM, MB, VID, and AD; graphicalabstract design, AD, RDM, and VID. All authors have read andagreed upon the final version of the manuscript.Conflict of Interest: The authors declare that the research was conducted in theabsence of any commercial or financial relationships that could be construed as apotential conflict of interest.Publisher’s Note: All claims expressed in this article are solely those of the authorsand do not necessarily represent those of their affiliated organizations, or those ofthe publisher, the editors and the reviewers. Any product that may be evaluated inthis article, or claim that may be made by its manufacturer, is not guaranteed orendorsed by the publisher.Copyright © 2022 De Marco, Dehshahri, Baiula and Dodero. This is an open-accessarticle distributed under the terms of the Creative Commons Attribution License (CCBY). The use, distribution or reproduction in other forums is permitted, provided theoriginal author(s) and the copyright owner(s) are credited and that the originalpublication in this journal is cited, in accordance with accepted academic practice.No use, distribution or reproduction is permitted which does not comply withthese terms.Frontiers in Chemistry | www.frontiersin.org June 2022 | Volume 10 | Article 9546182De Marco et al. Editorial: Integrin Ligands and their Bioconjugate Systems

Editorial: Integrin Ligands and Their Bioconjugate Systems: Synthesis, Conformation, and Biological Activity

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Editorial: Integrin Ligands and Their Bioconjugate Systems: Synthesis, Conformation, and Biological Activity

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