Wechselwirkung der Integrine mit chemisch modifizierten Peptiden

Urman S (2007)
Bielefeld: Universität.

Bielefeld Dissertation | German
Sewald, Norbert
Alternative Title
Interaction of integrines with chemically modified peptides
Summary (Dissertation of Sylwia Urman-2007) Integrins are cell surface receptors which are found on various cells in higher organisms. Through the high specific interactions with their natural ligands, they mediate a diversity of biological processes that are crucial for the correct progression of physiological phenomena. In this way, integrins participate in the regulation of embryogenesis, wound healing, bone functions or immune reaction. They can also participate in pathological processes. In this case integrins play an important role in tumor-induced angiogenesis, in chronic illnesses or tumor metastasis. During an infection with bacteria or viruses, integrins are involved in the molecular recognition. The aim of this work is the discovery of new peptidic integrin ligands. For this purpose various research projects were carried out. Specific interactions between integrins and ligands and the influence of chemically modified peptides on these interactions were investigated in detail. It has been supposed, that the binding epitope TQIDSPLN is responsible for the molecular recognition between integrin alpha4 beta1 and its natural ligand VCAM-1 (vascular cell adhesion molecule 1). The influence of peptides, which were designed according to a spatial screening approach, was investigated in this work. Furthermore, ADAM8 protein was investigated as integrin ligand. Fertilization, embryogenesis, and immune response of the organism are some of the pivotal processes that are regulated by the interactions of ADAM proteins with integrins. It has been shown by the means of flow cytometry, that this protein is a ligand of human integrins. In competition experiments cyclic KDM-peptides do not possess any inhibiting influence on interactions between the hADAM8 and integrins. Furthermore, the influence of cyclic KDK-hexapeptides on the homophilic interactions of murine ADAM8 was investigated. Predominantly, this work focuses on RGD-dependent ligands binding to integrins. The RGD-recognition motif represents one of the most important recognition sequences of integrins. It is presented on proteins of the extracellular space and on surface receptors of various cells. It has been shown that the incorporation of the conformational restricted beta-amino acid (beta-Acc) into the peptide backbone has led to a new potent ligand with higher selectivity to integrin alphaV beta3. The relative selectivity of the peptides c(RGD-(+)-beta-Acc-V) and c(RGD-(-)-beta-Acc-V) was estimated by the determination of the affinity of these peptides to integrin apha5 beta1. The peptide c(RGD-(+)-beta-Acc-V) was estimated in cell adhesion assays with WM115 cells and vitronectin. With an IC50-value of 20 nM it was tenfold more active than the known literature peptide c(RGDfV). The biological activity and selectivity of both peptides have been explained by correlating the structure analysis progressed by Gaus to known structure-activity relationships. Furthermore, an investigation of the interactions of bacterial protein CagL from Helicobacter pylori with human integrins was performed. Within the scope of this work it has been proved that the CagL protein is able to RGD-dependent binding on integrins and that these interactions can be inhibited by cyclic peptides. The results obtained have delivered insight in the multifunctional role CagL protein potentially plays during the infection of a host cell through H. pylori.

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Urman S. Wechselwirkung der Integrine mit chemisch modifizierten Peptiden. Bielefeld: Universität; 2007.
Urman, S. (2007). Wechselwirkung der Integrine mit chemisch modifizierten Peptiden. Bielefeld: Universität.
Urman, S. (2007). Wechselwirkung der Integrine mit chemisch modifizierten Peptiden. Bielefeld: Universität.
Urman, S., 2007. Wechselwirkung der Integrine mit chemisch modifizierten Peptiden, Bielefeld: Universität.
S. Urman, Wechselwirkung der Integrine mit chemisch modifizierten Peptiden, Bielefeld: Universität, 2007.
Urman, S.: Wechselwirkung der Integrine mit chemisch modifizierten Peptiden. Universität, Bielefeld (2007).
Urman, Sylwia. Wechselwirkung der Integrine mit chemisch modifizierten Peptiden. Bielefeld: Universität, 2007.
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