Thromb Haemost 2008; 99(05): 803-804
DOI: 10.1160/TH08-03-0194
Editorial Focus
Schattauer GmbH

Therapeutic integrin inhibition: Allosteric and activation-specific inhibition strategies may surpass the initial ligand-mimetic strategies

Ingo Ahrens
1   Baker Heart Research Institute, Melbourne, Australia
,
Karlheinz Peter
1   Baker Heart Research Institute, Melbourne, Australia
› Author Affiliations
Further Information

Publication History

Received 28 March 2008

Accepted 28 March 2008

Publication Date:
30 November 2017 (online)

 

 
  • References

  • 1 Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell 2002; 110: 673-687.
  • 2 Xiong JP, Stehle T, Diefenbach B. et al. Crystal structure of the extracellular segment of integrin v3. Science 2001; 294: 339-345.
  • 3 Xiao T, Takagi J, Coller BS. et al. Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics. Nature 2004; 432: 59-67.
  • 4 Luo BH, Carman CV, Springer TA. Structural basis of integrin regulation and signaling. Annu Rev Immunol 2007; 25: 619-647.
  • 5 O'Toole TE, Katagiri Y, Faull RJ. et al. Integrin cytoplasmic domains mediate inside-out signal transduction. J Cell Biol 1994; 124: 1047-1059.
  • 6 Peter K, O'Toole TE. Modulation of cell adhesion by changes in αLβ2 (LFA-1, CD11a/CD18) cytoplasmic domain/cytoskeleton interaction. J Exp Med 1995; 181: 315-326.
  • 7 Vinogradova O, Velyvis A, Velyviene A. et al. A structural mechanism of integrin αIIbβ3 "inside-out" activation as regulated by its cytoplasmic face. Cell 2002; 110: 587-597.
  • 8 Kim M, Carman CV, Springer TA. Bidirectional transmembrane signaling by cytoplasmic domain separation in integrins. Science 2003; 301: 1720-1725.
  • 9 Takagi J, Petre BM, Walz T. et al. Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling. Cell 2002; 110: 599-511.
  • 10 Lu CF, Springer TA. The β subunit cytoplasmic domain regulates the assembly and adhesiveness of integrin lymphocyte function-associated antigen-1. J Immunol 1997; 159: 268-278.
  • 11 Ahrens IG, Moran N, Aylward K. et al. Evidence for a differential functional regulation of the two β3 -integrins αVβ3 and αIIbβ3 . Exp Cell Res 2006; 312: 925-937.
  • 12 Coller BS, Folts JD, Smith SR. et al. Abolition of in vivo platelet thrombus formation in primates with monoclonal antibodies to the platelet GPIIb/IIIa receptor. Correlation with bleeding time, platelet aggregation, and blockade of GPIIb/IIIa receptors. Circulation 1989; 80: 1766-1774.
  • 13 Ahrens I, Bode C, Peter K. Inhibition of platelet activation and aggregation. Handb Exp Pharmacol 2005; 170: 443-462.
  • 14 Meadows TA, Bhatt DL. Clinical aspects of platelet inhibitors and thrombus formation. Circ Res 2007; 100: 1261-1275.
  • 15 Chew DP, Bhatt DL, Sapp S. et al. Increased mortality with oral platelet glycoprotein IIb/IIIa antagonists: a meta-analysis of phase III multicenter randomized trials. Circulation 2001; 103: 201-206.
  • 16 Bassler N, Loeffler C, Mangin P. et al. A mechanistic model for paradoxical platelet activation by ligand- mimetic αIIbβ3 (GPIIb/IIIa) antagonists. Arterioscler Thromb Vasc Biol 2007; 27: e9-15.
  • 17 Blue R, Murcia M, Karan C. et al. Application of high-throughput screening to identify a novel IIb-specific small- molecule inhibitor of αIIbβ3-mediated platelet interaction with fibrinogen. Blood 2008; 111: 1248-1256.
  • 18 Haas TA. Allosteric regulation of αIIbβ3 by β3 95–105. Thromb Haemost 2008; 99: 701-710.
  • 19 Shimaoka M, Springer TA. Therapeutic antagonists and conformational regulation of integrin function. Nat Rev Drug Discov 2003; 2: 703-716.
  • 20 Schwarz M, Meade G, Stoll P. et al. Conformationspecific blockade of the integrin GPIIb/IIIa: a novel antiplatelet strategy that selectively targets activated platelets. Circ Res 2006; 99: 25-33.
  • 21 Eisenhardt SU, Schwarz M, Schallner N. et al. Generation of activation-specific human anti-αMβ2 single-chain antibodies as potential diagnostic tools and therapeutic agents. Blood 2007; 109: 3521-3528.