Synthesis, conformational analysis and biological activities of lanthionine analogs of a cell adhesion modulator.
Cell adhesion is critical for many biological processes, such as hemostasis, wound healing, tumor metastasis and inflammation. Integrins are important mediators of cell adhesion. The integrin alpha4beta1, also known as VLA-4, is a cell surface receptor involved in inflammation. A cyclic peptide, 1-FCA-Arg-c[Cys-Asp-Thz-Cys]-OH, is a potent antagonist to VLA-4 with an IC50 of 2.4 nM. In the current study, we synthesized the lanthionine analogs of 1-FCA-Arg-c[Cys-Asp-Thz-Cys]-OH and determined the conformations of both the parent compound and its lanthionine analog in solution by NMR and computer simulations. The lanthionine analog retains its selectivity to VLA-4 with high nanomolar potency. Both molecules adopt similar topological arrangements in their conformations, while some important differences remain in the sulfur bridge region, which may cause the difference in potency.
Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla 92093-0343, USA.
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D000409:Alanine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D003198:Computer Simulation; D006801:Humans; D020128:Inhibitory Concentration 50; D039041:Integrin alpha4beta1; D016023:Integrins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D011487:Protein Conformation; D016201:Receptors, Lymphocyte Homing / Q000037:antagonists & inhibitors; D013440:Sulfides
D015815:Cell Adhesion Molecules; D039041:Integrin alpha4beta1; D016023:Integrins; D010455:Peptides; D016201:Receptors, Lymphocyte Homing; D013440:Sulfides; C001520:lanthionine; D000409:Alanine