Role of the natural CXCR4 antagonist ALB408-423 in health and disease
Zusammenfassung der Projektergebnisse
CXCL12-CXCR4 signaling controls multiple physiological processes and its dysregulation is associated with cancers and inflammatory diseases. We have identified a 16 amino acid fragment of serum albumin as an effective and highly specific CXCR4 antagonist. The endogenous peptide, termed EPI-X4, is evolutionarily conserved and generated from the highly abundant albumin precursor by pH-regulated proteases. EPI-X4 forms an unusual lasso-like structure and antagonizes CXCL12-induced tumor cell migration, mobilizes stem cells, and suppresses inflammatory responses in mice. Furthermore, the peptide is abundant in the urine of patients with inflammatory kidney diseases and may serve as a biomarker. The identification of an endogenous antagonist of CXCR4 signaling opens up exciting possibilities for future research. The proteolytic generation of a bioactive peptide from an abundant precursor protein represents a novel concept for the regulation of GPCRs, which are the largest and most diverse group of membrane receptors in eukaryotes and targets of almost half of all modern drugs. Our data show that this regulation of CXCR4 activity is conserved from mice to humans, and it will be interesting to determine whether other GPCRs are regulated by similar means. Ongoing work aims to clarify the role of EPI-X4 in HIV-1 sexual and vertical transmission, to understand its role in the body, and to develop EPI-X4 derivatives with improved stability and anto-CXCR4 activity as novel drugs for the therapy of CXCR4 linked diseases. This research is integrated into the CRC1279 “Exploiting the human peptidome for novel antimicrobial and anticancer agents”. https://www.n-tv.de/wissen/Koerpereigener-Stoff-blockiert-HI-Viren-article15039891.html https://healthcare-in-europe.com/de/story/14336-neuer-koerpereigener-hiv-hemmstoff-entdeckt.html http://www.aachener-nachrichten.de/ratgeber/gesundheit/forscher-finden-peptid-gegen-hiv-krebs-und-asthma-1.1105558 https://www.aerzteblatt.de/nachrichten/62793/Koerpereigenes-Peptid-blockiert-HIV
Projektbezogene Publikationen (Auswahl)
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Discovery and characterization of an endogenous CXCR4 antagonist. Cell Rep. 2015 May 5;11(5):737-47
Zirafi O, Kim KA, Ständker L, Mohr KB, Sauter D, Heigele A, Kluge SF, Wiercinska E, Chudziak D, Richter R, Moepps B, Gierschik P, Vas V, Geiger H, Lamla M, Weil T, Burster T, Zgraja A, Daubeuf F, Frossard N, Hachet-Haas M, Heunisch F, Reichetzeder C, Galzi JL, Pérez-Castells J, Canales-Mayordomo A, Jiménez-Barbero J, Giménez-Gallego G, Schneider M, Shorter J, Telenti A, Hocher B, Forssmann WG, Bonig H, Kirchhoff F, Münch J
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EPI-X4, a novel endogenous antagonist of CXCR4. Oncotarget. 2015 Nov 3;6(34):35137-8
Buske C, Kirchhoff F, Münch J
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Sandwich enzyme-linked immunosorbent assay for the quantification of human serum albumin fragment 408-423 in bodily fluids. Anal Biochem. 2015 May 1;476:29-35
Mohr KB, Zirafi O, Hennies M, Wiese S, Kirchhoff F, Münch J
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Evaluation of EPI-X4 as a urinary peptide biomarker for diagnosis and prognosis of late acute GvHD. Bone Marrow Transplant. 2016 Aug;51(8):1137-9
Müller JA, Zirafi O, Roan NR, Lee SJ, Münch J
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Proteolytic processing of human serum albumin generates EPI- X4, an endogenous antagonist of CXCR4. J Leukoc Biol. 2016 Jun;99(6):863-8
Zirafi O, Hermann PC, Münch J
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A cxc chemokine receptor 4 (cxcr4) antagonistic polypeptide. WO2009004054; Anmeldenummer: PCT/EP2008/058566; Veröffentlichungsdatum: 6. Apr. 2017
Wolf-Georg Forssmann, Frank Kirchhoff, Jan Münch, Ludger Ständker
