tailieunhanh - Báo cáo khoa học: Grafting of thrombopoietin-mimetic peptides into cystine knot miniproteins yields high-affinity thrombopoietin antagonists and agonists

Thrombopoietin is the primary regulator of platelet production. We exploi-ted two naturally occurring miniproteins of the inhibitor cystine knot fam-ily as stable and rigid scaffolds for the incorporation of peptide sequences that have been shown to act as high-affinity thrombopoietin antagonists. Several miniproteins that antagonistically block thrombopoietin-mediated receptor activation were identified using a microscale reporter assay. | ễFEBS Journal Grafting of thrombopoietin-mimetic peptides into cystine knot miniproteins yields high-affinity thrombopoietin antagonists and agonists Sebastian Krause1 Hans-Ulrich Schmoldt2 Alexander Wentzel3 1 Matthias Ballmaier4 Karlheinz Friedrich1 and Harald Kolmar2 3 1 University of Jena MedicalSchool Institute of Biochemistry Jena Germany 2 Department of Molecular Genetics Georg-August-University Gottingen Germany 3 Selecore GmbH Gottingen Germany 4 Department of Pediatric Hematology and Oncology Medizinische Hochschule Hannover Germany Keywords c-Mplreceptor cystine knot proteins peptide agonist thrombocytopenia thrombopoietin mimetics Correspondence H. Kolmar Clemens-Schopf Institute of Organic Chemistry and Biochemistry Darmstadt University of Technology Petersenstr. 22 D-64287 Darmstadt Germany Fax 49 6151 16 5399 Tel 49 6151 16 3657 E-mail Kolmar@ Present address Institutt for Bioteknologi NTNU Trondheim Norway Thrombopoietin is the primary regulator of platelet production. We exploited two naturally occurring miniproteins of the inhibitor cystine knot family as stable and rigid scaffolds for the incorporation of peptide sequences that have been shown to act as high-affinity thrombopoietin antagonists. Several miniproteins that antagonistically block thrombopoietin-mediated receptor activation were identified using a microscale reporter assay. Covalent miniprotein dimerization yielded potent bivalent c-Mpl receptor agonists with EC50 values in the low nanomolar or picomolar range. One selected miniprotein-derived thrombopoietin agonist was almost as active as natural thrombopoietin with regard to stimulation of megakaryocyte colony formation from human bone marrow mononuclear cells and elicited doubling of platelet counts in mice. Our data suggest that dimeric cystine knot miniproteins have considerable potential for the future development of small and stable receptor agonists. This approach may provide a promising strategy for .

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