Skip to main content
SpringerLink
Log in

The Therapeutic Potential of I-Domain Integrins

  • Chapter
  • First Online:
I Domain Integrins

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 819))

Abstract

Due to their role in processes central to cancer and autoimmune disease I-domain integrins are an attractive drug target. Both antibodies and small molecule antagonists have been discovered and tested in the clinic. Much of the effort has focused on αLβ2 antagonists. Maybe the most successful was the monoclonal antibody efalizumab, which was approved for the treatment of psoriasis but subsequently withdrawn from the market due to the occurrence of a serious adverse effect (progressive multifocal leukoencephalopathy). Other monoclonal antibodies were tested for the treatment of reperfusion injury, post-myocardial infarction, but failed to progress due to lack of efficacy. New potent small molecule inhibitors of αv integrins are promising reagents for treating fibrotic disease. Small molecule inhibitors targeting collagen-binding integrins have been discovered and future work will focus on identifying molecules selectively targeting each of the collagen receptors and identifying appropriate target diseases for future clinical studies.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. IMPACT investigators (1997) Randomised placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT-II. Integrilin to minimise platelet aggregation and coronary thrombosis-II. Lancet 349:1422--1428.

    Google Scholar 

  2. Aggeli AS, Kitsiou PV, Tzinia AK, Boutaud A, Hudson BG, Tsilibary EC (2009) Selective binding of integrins from different renal cell types to the NC1 domain of alpha3 and alpha1 chains of type IV collagen. J Nephrol 22:130–136

    CAS  PubMed  Google Scholar 

  3. Aikio M, Alahuhta I, Nurmenniemi S, Suojanen J, Palovuori R, Teppo S et al (2012) Arresten, a collagen-derived angiogenesis inhibitor, suppresses invasion of squamous cell carcinoma. PLoS ONE 7:e51044

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Arlinghaus FT, Eble JA (2013) The Collagen-binding integrin α2β1 is a novel interaction partner of the Trimeresurus flavoviridis venom protein flavocetin-A. J Biol Chem 288:947–955

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Arlinghaus FT, Momic T, Ammar NA, Shai E, Spectre G, Varon D et al (2013) Identification of α2β1 integrin inhibitor VP-i with anti-platelet properties in the venom of Vipera palaestinae. Toxicon 64:96–105

    CAS  PubMed  Google Scholar 

  6. Avraamides CJ, Garmy-Susini B, Varner JA (2008) Integrins in angiogenesis and lymphangiogenesis. Nat Rev Cancer 8:604–617

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Baran KW, Nguyen M, McKendall GR, Lambrew CT, Dykstra G, Palmeri ST et al (2001) Double-blind, randomized trial of an anti-CD18 antibody in conjunction with recombinant tissue plasminogen activator for acute myocardial infarction: limitation of myocardial infarction following thrombolysis in acute myocardial infarction (LIMIT AMI) study. Circulation 104:2778–2783

    CAS  PubMed  Google Scholar 

  8. Bellahcene A, Castronovo V, Ogbureke KUE, Fisher LW, Fedarko NS (2008) Small integrin-binding ligand N-linked glycoproteins (SIBLINGs): multifunctional proteins in cancer. Nat Rev Cancer 8:212–226

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Bennett J (2006) Natalizumab and progressive multifocal leukoencephalopathy: migrating towards safe adhesion molecule therapy in multiple sclerosis. Neurol Res 28:291–298

    CAS  PubMed  Google Scholar 

  10. Boisvert M, Chetoui N, Gendron S, Aoudjit F (2010) α2β1 integrin is the major collagen-binding integrin expressed on human Th17 cells. Eur J Immunol 40:2710–2719

    CAS  PubMed  Google Scholar 

  11. Borza CM, Pozzi A, Borza D-B, Pedchenko V, Hellmark T, Hudson BG et al (2006) Integrin a3b1, a novel receptor for α3(IV) noncollagenous domain and a trans-dominant inhibitor for integrin αvβ3. J Biol Chem 281:20932–20939

    CAS  PubMed  Google Scholar 

  12. Bowen JD, Petersdorf SH, Richards TL, Maravilla KR, Dale DC, Price TH et al (1998) Phase I study of a humanized anti-CD11/CD18 monoclonal antibody in multiple sclerosis[ast]. Clin Pharmacol Ther 64:339–346

    CAS  PubMed  Google Scholar 

  13. Bracht T, Figueiredo de Rezende F, Stetefeld J, Sorokin LM, Eble JA (2011) Monoclonal antibodies reveal the alteration of the rhodocetin structure upon α2β1 integrin binding. Biochem J 440:1–11

    CAS  PubMed  Google Scholar 

  14. Brennan MP, Moriarty RD, Grennan S, Chubb AJ, Cox D (2008) C-reactive protein binds to αIIbβ3. J Thromb Haemost 6:1239–1241

    CAS  PubMed  Google Scholar 

  15. Brown MC, Eble JA, Calvete JJ, Marcinkiewicz C (2009) Structural requirements of KTS-disintegrins for inhibition of α1β1 integrin. Biochem J 417:95–101

    CAS  PubMed  Google Scholar 

  16. Bryant JE, Shamhart PE, Luther DJ, Olson ER, Koshy JC, Costic DJ et al (2009) Cardiac myofibroblast differentiation is attenuated by α3 integrin blockade: potential role in post-MI remodeling. J Mol Cell Cardiol 46:186–192

    CAS  PubMed  Google Scholar 

  17. Bucolo C, Maltese A, Maugeri F, Ward K, Baiula M, Spartà A et al (2008) New coumarin-based anti-inflammatory drug: putative antagonist of the integrins αLβ2 and αMβ2. J Pharm Pharmacol 60:1473–1479

    CAS  PubMed  Google Scholar 

  18. Calvete J, Marcinkiewicz C, Sanz L (2007) KTS and RTS-disintegrins: anti-angiogenic viper venom peptides specifically targeting the α1β 1 integrin. Curr Pharm Des 13:2853–2859

    CAS  PubMed  Google Scholar 

  19. Camper L, Holmvall K, Wängnerud C, Aszódi A, Lundgren-Akerlund E (2001) Distribution of the collagen-binding integrin α10β1 during mouse development. Cell Tissue Res 306:107–116

    CAS  PubMed  Google Scholar 

  20. Champe M, McIntyre BW, Berman PW (1995) Monoclonal antibodies that block the activity of leukocyte function-associated antigen 1 recognize three discrete epitopes in the inserted domain of CD11a. J Biol Chem 270:1388–1394

    CAS  PubMed  Google Scholar 

  21. Chen W, Harbeck MC, Zhang W, Jacobson JR (2013) MicroRNA regulation of integrins. Transl Res 162:133–143

    CAS  PubMed  Google Scholar 

  22. Clark LA, Boriack-Sjodin PA, Eldredge J, Fitch C, Friedman B, Hanf KJ et al (2006) Affinity enhancement of an in vivo matured therapeutic antibody using structure-based computational design. Protein Sci 15:949–960

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Clemetson K, Clemetson J (2007) Collagen receptors as potential targets for novel anti-platelet agents. Curr Pharm Des 13:2673–2683

    CAS  PubMed  Google Scholar 

  24. Cox D (2004) Oral GPIIb/IIIa antagonists: what went wrong? Curr Pharm Des 10:1587–1596

    CAS  PubMed  Google Scholar 

  25. Cox D, Brennan M, Moran N (2010) Integrins as therapeutic targets: lessons and opportunities. Nat Rev Drug Discov 9:804–820

    CAS  PubMed  Google Scholar 

  26. Cox D, Smith R, Quinn M, Theroux P, Crean P, Fitzgerald DJ (2000) Evidence of platelet activation during treatment with a GPIIb/IIIa antagonist in patients presenting with acute coronary syndromes. J Am Coll Cardiol 36:1514–1519

    CAS  PubMed  Google Scholar 

  27. Crump MP, Ceska TA, Spyracopoulos L, Henry A, Archibald SC, Alexander R et al (2004) Structure of an allosteric inhibitor of LFA-1 bound to the I-domain studied by crystallography, NMR, and calorimetry. Biochemistry 43:2394–2404

    CAS  PubMed  Google Scholar 

  28. Dassanayake RP, Maheswaran SK, Srikumaran S (2007) Monomeric expression of bovine b2-integrin subunits reveals their role in Mannheimia haemolytica leukotoxin-induced biological effects. Infect Immun 75:5004–5010

    CAS  PubMed Central  PubMed  Google Scholar 

  29. Dedrick RL, Walicke P, Garovoy M (2002) Anti-adhesion antibodies: efalizumab, a humanized anti-CD11a monoclonal antibody. Transpl Immunol 9:181–186

    CAS  PubMed  Google Scholar 

  30. Desgrosellier JS, Cheresh DA (2010) Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer 10:9–22

    CAS  PubMed  Google Scholar 

  31. Dileepan T, Kachlany SC, Balashova NV, Patel J, Maheswaran SK (2007) Human CD18 is the functional receptor for Aggregatibacter actinomycetemcomitans leukotoxin. Infect Immun 75:4851–4856

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Dodd DS, Sheriff S, Chang CJ, Stetsko DK, Phillips LM, Zhang Y et al (2007) Design of LFA-1 antagonists based on a 2,3-dihydro-1H-pyrrolizin-5(7aH)-one scaffold. Bioorgan Med Chem Lett 17:1908–1911

    CAS  Google Scholar 

  33. Dove A (2000) CD18 trials disappoint again. Nat Biotech 18:817–818

    CAS  Google Scholar 

  34. Dubertret L, Sterry W, Bos JD, Chimenti S, Shumack S, Larsen CG et al (2006) CLinical experience acquired with the efalizumab (Raptiva) (CLEAR) trial in patients with moderate-to-severe plaque psoriasis: results from a phase III international randomized, placebo-controlled trial. Br J Dermatol 155:170–181

    CAS  PubMed  Google Scholar 

  35. Eble JA, Niland S, Bracht T, Mormann M, Peter-Katalinic J, Pohlentz G et al. (2009) The alpha2beta1 integrin-specific antagonist rhodocetin is a cruciform, heterotetrameric molecule. FASEB J 23: 2917–2927

    Google Scholar 

  36. Emsley J, King SL, Bergelson JM, Liddington RC (1997) Crystal structure of the I domain from integrin α2β1. J Biol Chem 272:28512–28517

    CAS  PubMed  Google Scholar 

  37. Emsley J, Knight CG, Farndale RW, Barnes MJ, Liddington RC (2000) Structural basis of collagen recognition by integrin α2β1. Cell 101:47–56

    CAS  PubMed  Google Scholar 

  38. Eskan MA, Jotwani R, Abe T, Chmelar J, Lim J-H, Liang S et al (2012) The leukocyte integrin antagonist Del-1 inhibits IL-17-mediated inflammatory bone loss. Nat Immunol 13:465–473

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Fabene PF, Mora GN, Martinello M, Rossi B, Merigo F, Ottoboni L et al (2008) A role for leukocyte-endothelial adhesion mechanisms in epilepsy. Nat Med 14:1377–1383

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Faridi MH, Altintas MM, Gomez C, Duque JC, Vazquez-Padron RI, Gupta V (2013) Small molecule agonists of integrin CD11b/CD18 do not induce global conformational changes and are significantly better than activating antibodies in reducing vascular injury. Biochimica et Biophysica Acta (BBA) - General Subjects 1830:3696–3710

    Google Scholar 

  41. Farstad I, Halstensen T, Lien B, Kilshaw P, Lazarovits A, Brandtzaeg P et al (1996) Distribution of β7 integrins in human intestinal mucosa and organized gut-associated lymphoid tissue. Immunology 89:227–237

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Faxon DP, Gibbons RJ, Chronos NAF, Gurbel PA, Sheehan F (2002) The effect of blockade of the CD11/CD18 integrin receptor on infarct size in patients with acute myocardial infarction treated with direct angioplasty: the results of the HALT-MI study. J Am Coll Cardiol 40:1199–1204

    CAS  PubMed  Google Scholar 

  43. Fleming FE, Graham KL, Taniguchi K, Takada Y, Coulson BS (2007) Rotavirus-neutralizing antibodies inhibit virus binding to integrins α2β1 and α4β1. Arch Virol 152:1087

    CAS  PubMed  Google Scholar 

  44. Fukuda K, Saikawa Y, Yagi H, Wada N, Takahashi T, Kitagawa Y (2012) Role of integrin α1 subunits in gastric cancer patients with peritoneal dissemination. Mol Med Rep 5:336–340

    CAS  PubMed  Google Scholar 

  45. Gadek TR, Burdick DJ, McDowell RS, Stanley MS, Marsters JC Jr, Paris KJ et al (2002) Generation of an LFA-1 antagonist by the transfer of the ICAM-1 immunoregulatory epitope to a small molecule. Science 295:1086–1089

    CAS  PubMed  Google Scholar 

  46. Gadek TR, McDowell RS (2003) Discovery of small molecule leads in a biotechnology datastream. Drug Discovery Today 8:545–550

    CAS  PubMed  Google Scholar 

  47. Gonzalez-Amaro R, Mittelbrunn M, Sanchez-Madrid F (2005) Therapeutic anti-integrin (α4 and αL) monoclonal antibodies: two-edged swords? Immunology 116:289–296

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Gordon KB, Papp KA, Hamilton TK, Walicke PA, Dummer W, Li N et al (2003) Efalizumab for patients with moderate to severe plaque psoriasis: a randomized controlled trial. J Am Med Assoc 290:3073–3080

    CAS  Google Scholar 

  49. Gottlieb AB, Krueger JG, Wittkowski K, Dedrick R, Walicke P, Garovoy M (2002) Psoriasis as a model for t-cell–mediated disease: immunobiologic and clinical effects of treatment with multiple doses of efalizumab, an anti–cd11a antibody. Arch Dermatol 138:591–600

    CAS  PubMed  Google Scholar 

  50. Goyal A, Pal N, Concannon M, Paul M, Doran M, Poluzzi C et al (2011) Endorepellin, the angiostatic module of perlecan, interacts with both the α2β1 integrin and vascular endothelial growth factor receptor 2 (VEGFR2): a dual receptor antagonism. J Biol Chem 286:25947–25962

    CAS  PubMed Central  PubMed  Google Scholar 

  51. Graham KL, Fleming FE, Halasz P, Hewish MJ, Nagesha HS, Holmes IH et al (2005) Rotaviruses interact with α4β7 and α4β1 integrins by binding the same integrin domains as natural ligands. J Gen Virol 86:3397–3408

    CAS  PubMed  Google Scholar 

  52. Graham KL, Halasz P, Tan Y, Hewish MJ, Takada Y, Mackow ER et al (2003) Integrin-using rotaviruses bind α2β1 integrin α2 I domain via VP4 DGE sequence and recognize αXβ2 and αVβ3 by using VP7 during cell entry. J Virol 77:9969–9978

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Harlan JM, Winn RK (2002) Leukocyte-endothelial interactions: clinical trials of anti-adhesion therapy. Crit Care Med 30:S214–S219

    CAS  PubMed  Google Scholar 

  54. Havrdova E, Galetta S, Hutchinson M, Stefoski D, Bates D, Polman CH et al (2009) Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the natalizumab safety and efficacy in relapsing-remitting multiple sclerosis (AFFIRM) study. Lancet Neurol 8:254–260

    PubMed  Google Scholar 

  55. Horii K, Okuda D, Morita T, Mizuno H (2004) Crystal structure of EMS16 in complex with the integrin alpha2-I domain. J Mol Biol 341:519–527

    CAS  PubMed  Google Scholar 

  56. Houimel M, Mazzucchelli L (2012) Random phage-epitope library based identification of a peptide antagonist of Mac-1 β2 integrin ligand binding. Matrix Biol 31:66–77

    CAS  PubMed  Google Scholar 

  57. Huang C, Ogawa R (2012) Fibroproliferative disorders and their mechanobiology. Connect Tissue Res 53:187–196

    CAS  PubMed  Google Scholar 

  58. Jia W, Li H, He Y-W (2005) The extracellular matrix protein mindin serves as an integrin ligand and is critical for inflammatory cell recruitment. Blood 106:3854–3859

    CAS  PubMed Central  PubMed  Google Scholar 

  59. Jin H, Varner J (2004) Integrins: roles in cancer development and as treatment targets. Br J Cancer 90:561–565

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Kallen J, Welzenbach K, Ramage P, Geyl D, Kriwacki R, Legge G et al (1999) Structural basis for LFA-1 inhibition upon lovastatin binding to the CD11a I-domain. J Mol Biol 292:1–9

    CAS  PubMed  Google Scholar 

  61. Karpusas M, Ferrant J, Weinreb PH, Carmillo A, Taylor FR, Garber EA (2003) Crystal structure of the α1β1 integrin I domain in complex with an antibody Fab fragment. J Mol Biol 327:1031–1041

    CAS  PubMed  Google Scholar 

  62. Keating SM, Clark KR, Stefanich LD, Arellano F, Edwards CP, Bodary SC et al (2006) Competition between intercellular adhesion molecule-1 and a small-molecule antagonist for a common binding site on the aL subunit of lymphocyte function-associated antigen-1. Protein Sci 15:290–303

    CAS  PubMed Central  PubMed  Google Scholar 

  63. Kelly TA, Jeanfavre DD, McNeil DW, Woska JR Jr, Reilly PL, Mainolfi EA et al (1999) Cutting edge: a small molecule antagonist of LFA-1-mediated cell adhesion. J Immunol 163:5173–5177

    CAS  PubMed  Google Scholar 

  64. Kenakin T (2005) New concepts in drug discovery: collateral efficacy and permissive antagonism. Nat Rev Drug Discov 4:919–927

    CAS  PubMed  Google Scholar 

  65. Khojasteh SC, Leipold DD, Lai F, La H, Baumgardner MJ, Desino KE et al (2008) Preclinical absorption, distribution, metabolism and excretion (ADME) characterization of ICAM1988, an LFA-1/ICAM antagonist, and its prodrug. Xenobiotica 38:340–352

    CAS  PubMed  Google Scholar 

  66. Kim M, Ogawa M, Fujita Y, Yoshikawa Y, Nagai T, Koyama T et al (2009) Bacteria hijack integrin-linked kinase to stabilize focal adhesions and block cell detachment. Nature 459:578–582

    CAS  PubMed  Google Scholar 

  67. Kisiel DG, Calvete JJ, Katzhendler J, Fertala A, Lazarovici P, Marcinkiewicz C (2004) Structural determinants of the selectivity of KTS-disintegrins for the α1β1 integrin. FEBS Lett 577:478–482

    CAS  PubMed  Google Scholar 

  68. Koivunen E, Wang B, Ruoslahti E (1994) Isolation of a highly specific ligand for the α5β1 integrin from a phage display library. J Cell Biol 124:373–380

    CAS  PubMed  Google Scholar 

  69. Korman BD, Tyler KL, Korman NJ (2009) Progressive multifocal leukoencephalopathy, efalizumab, and immunosuppression: a cautionary tale for dermatologists. Arch Dermatol 145:937–942

    PubMed  Google Scholar 

  70. Lebwohl M, Tyring SK, Hamilton TK, Toth D, Glazer S, Tawfik NH et al (2003) A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. N Engl J Med 349:2004–2013

    CAS  PubMed  Google Scholar 

  71. Lee H-J, Kim S-Y, Koh J-M, Bok J, Kim K-J, Kim K-S et al (2007) Polymorphisms and haplotypes of integrin a1 (ITGA1) are associated with bone mineral density and fracture risk in postmenopausal Koreans. Bone 41:979–986

    CAS  PubMed  Google Scholar 

  72. Lees KR, Diener H-C, Asplund K, Krams M, UK-279 -SI (2003) UK-279,276, a neutrophil inhibitory glycoprotein, in acute stroke: tolerability and pharmacokinetics. Stroke 34:1704–1709

    Google Scholar 

  73. Lehmann J, Huehn J, de la Rosa M, Maszyna F, Kretschmer U, Krenn V et al (2002) Expression of the integrin αEβ7 identifies unique subsets of CD25 + as well as CD25- regulatory T cells. PNAS 99:13031–13036

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Leonardi C, Menter A, Hamilton T, Caro I, Xing B, Gottlieb AB (2008) Efalizumab: results of a 3-year continuous dosing study for the long-term control of psoriasis. Br J Dermatol 158:1107–1116

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Leonardi CL, Papp KA, Gordon KB, Menter A, Feldman SR, Caro I et al (2005) Extended efalizumab therapy improves chronic plaque psoriasis: results from a randomized phase III trial. J Am Acad Dermatol 52:425–433

    PubMed  Google Scholar 

  76. Li Y, Cao C, Jia W, Yu L, Mo M, Wang Q et al (2009) Structure of the F-spondin domain of mindin, an integrin ligand and pattern recognition molecule. EMBO J 28:286–297

    PubMed Central  PubMed  Google Scholar 

  77. Li S, Wang H, Peng B, Zhang M, Zhang D, Hou S et al (2009) Efalizumab binding to the LFA-1 αL I domain blocks ICAM-1 binding via steric hindrance. Proc Natl Acad Sci U S A 106:4349–4354

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Liu G, Huth JR, Olejniczak ET, Mendoza R, DeVries P, Leitza S et al (2001) Novel p-arylthio cinnamides as antagonists of leukocyte function-associated antigen-1/intracellular adhesion molecule-1. Interaction. 2. Mechanism of inhibition and structure-based improvement of pharmaceutical properties. J Med Chem 44:1202–1210

    CAS  PubMed  Google Scholar 

  79. Maiguel D, Faridi MH, Wei C, Kuwano Y, Balla KM, Hernandez D et al (2011) Small Molecule-mediated activation of the integrin CD11b/CD18 Reduces inflammatory disease. Sci. Signal 4:ra57

    Google Scholar 

  80. Marcinkiewicz C, Lobb RR, Marcinkiewicz MM, Daniel JL, Smith JB, Dangelmaier C et al (2000) Isolation and characterization of EMS16, a C-lectin type protein from Echis multisquamatus venom, a potent and selective inhibitor of the α2β1 integrin†. Biochemistry 39:9859–9867

    CAS  PubMed  Google Scholar 

  81. Marcinkiewicz C, Weinreb PH, Calvete JJ, Kisiel DG, Mousa SA, Tuszynski GP et al (2003) Obtustatin: a potent selective inhibitor of α1β1 integrin in vitro and angiogenesis in vivo. Cancer Res 63:2020–2023

    CAS  PubMed  Google Scholar 

  82. McDowall A, Leitinger B, Stanley P, Bates PA, Randi AM, Hogg N (1998) The I domain of integrin leukocyte function-associated antigen-1 is involved in a conformational change leading to high affinity binding to ligand intercellular adhesion molecule 1 (ICAM-1). J Biol Chem 273:27396–27403

    CAS  PubMed  Google Scholar 

  83. Micklem K, Sim R (1985) Isolation of complement-fragment-iC3b-binding proteins by affinity chromatography. The identification of p150,95 as an iC3b-binding protein. Biochem J 231:233–236

    CAS  PubMed Central  PubMed  Google Scholar 

  84. Miller MW, Basra S, Kulp DW, Billings PC, Choi S, Beavers MP et al (2009) Small-molecule inhibitors of integrin a2b1 that prevent pathological thrombus formation via an allosteric mechanism. Proc Natl Acad Sci 106:719–724

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Moir LM, Black JL, Krymskaya VP (2012) TSC2 modulates cell adhesion and migration via integrin-α1β1. Am J Physiol Lung Cell Mol Physiol 303:L703–L710

    CAS  PubMed Central  PubMed  Google Scholar 

  86. Momic T, Cohen G, Reich R, Arlinghaus FT, Eble JA, Marcinkiewicz C et al (2012) Vixapatin (VP12), a C-type lectin-protein from Vipera xantina palestinae venom: characterization as a novel anti-angiogenic compound. Toxins 4:862–877

    CAS  PubMed Central  PubMed  Google Scholar 

  87. Mongiat M, Sweeney SM, San Antonio JD, Fu J, Iozzo RV (2003) Endorepellin, a novel inhibitor of angiogenesis derived from the c terminus of perlecan. J Biol Chem 278:4238–4249

    CAS  PubMed  Google Scholar 

  88. Moreno-Murciano MP, Monleón D, Calvete JJ, Celda B, Marcinkiewicz C (2003) Amino acid sequence and homology modeling of obtustatin, a novel non-RGD-containing short disintegrin isolated from the venom of Vipera lebetina obtusa. Protein Sci 12:366–371

    CAS  PubMed Central  PubMed  Google Scholar 

  89. Morova J, Osicka R, Masin J, Sebo P (2008) RTX cytotoxins recognize b2 integrin receptors through N-linked oligosaccharides. Proc Nat Acad Sci 105:5355–5360

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Moschos S, Drogowski L, Reppert S, Kirkwood J (2007) Integrins and cancer. Oncology (Williston Park) 21:13–20

    Google Scholar 

  91. Munger JS, Harpel JG, Giancotti FG, Rifkin DB (1998) Interactions between growth factors and integrins: latent forms of transforming growth factor-beta are ligands for the integrin αVβ1. Mol Biol Cell 9:2627–2638

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Nissinen L, Koivunen J, Käpylä J, Salmela M, Nieminen J, Jokinen J et al (2012) Novel α2β1 integrin inhibitors reveal that integrin binding to collagen under shear stress conditions does not require receptor preactivation. J Biol Chem 287:44694–44702

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Nissinen L, Pentikäinen O, Jouppila A, Käpylä J, Ojala M, Nieminen J et al (2010) A small-molecule inhibitor of integrin alpha2 beta1 introduces a new strategy for antithrombotic therapy. Thromb Haemost 103:387–397

    CAS  PubMed  Google Scholar 

  94. Olfa K-Z, Jose L, Salma D, Amine B, Najet SA, Nicolas A et al (2005) Lebestatin, a disintegrin from Macrovipera venom, inhibits integrin-mediated cell adhesion, migration and angiogenesis. Lab Invest 85:1507–1516

    CAS  PubMed  Google Scholar 

  95. Ortonne JP, Shear N, Shumack S, Henninger E (2005) Impact of efalizumab on patient-reported outcomes in high-need psoriasis patients: results of the international, randomized, placebo-controlled Phase III clinical experience acquired with raptiva (CLEAR) trial [NCT00256139]. BMC Dermatol 5:13

    PubMed Central  PubMed  Google Scholar 

  96. Panzenbeck MJ, Jeanfavre DD, Kelly TA, Lemieux R, Nabozny G, Reilly PL et al (2006) An orally active, primate selective antagonist of LFA-1 inhibits delayed-type hypersensitivity in a humanized-mouse model. Eur J Pharmacol 534:233–240

    CAS  PubMed  Google Scholar 

  97. Paskowitz DM, Nguyen QD, Gehlbach P, Handa JT, Solomon S, Stark W et al (2012) Safety, tolerability, and bioavailability of topical SAR 1118, a novel antagonist of lymphocyte function-associated antigen-1: a phase 1b study. Eye 26:944–949

    CAS  PubMed Central  PubMed  Google Scholar 

  98. Patwardhan AP, Pulgam VR, Zhang Y, Wulff WD (2005) Highly diastereoselective alkylation of aziridine-2-carboxylate esters: enantioselective synthesis of LFA-1 antagonist BIRT-377. Angew Chem Int Ed 44:6169–6172

    CAS  Google Scholar 

  99. Polman CH, O’Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH et al (2006) A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 354:899–910

    CAS  PubMed  Google Scholar 

  100. Popova SN, Rodriguez-Sánchez B, Lidén Å, Betsholtz C, van den Bos T, Gullberg D (2004) The mesenchymal α11β1 integrin attenuates PDGF-BB-stimulated chemotaxis of embryonic fibroblasts on collagens. Dev Biol 270:427–442

    CAS  PubMed  Google Scholar 

  101. Potin D, Launay M, Monatlik F, Malabre P, Fabreguettes M, Fouquet A et al (2006) Discovery and development of 5-[(5S,9R)-9- (4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1- methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non- 7-yl-methyl]-3-thiophenecarboxylic Acid (BMS-587101)-a small molecule antagonist leukocyte function associated antigen-1. J Med Chem 49:6946–6949

    CAS  PubMed  Google Scholar 

  102. Potin D, Launay M, Nicolai E, Fabreguette M, Malabre P, Caussade F et al (2005) De novo design, synthesis, and in vitro activity of LFA-1 antagonists based on a bicyclic[5.5] hydantoin scaffold. Bioorg Med Chem Lett 15:1161–1164

    CAS  PubMed  Google Scholar 

  103. Ramirez NE, Zhang Z, Madamanchi A, Boyd KL, x, Rear LD et al (2011) The α2β1 integrin is a metastasis suppressor in mouse models and human cancer. J Clin Invest 121:226–237

    Google Scholar 

  104. Reynolds AR, Hart IR, Watson AR, Welti JC, Silva RG, Robinson SD et al (2009) Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors. Nat Med 15:392–400

    CAS  PubMed  Google Scholar 

  105. Rhee P, Morris J, Durham R, Hauser C, Cipolle M, Wilson R et al (2000) Recombinant humanized monoclonal antibody against CD18 (rhuMAb CD18) in traumatic hemorrhagic shock: results of a phase II clinical trial. Traumatic shock group. J Trauma 49:611–619

    CAS  PubMed  Google Scholar 

  106. Rice GPA, Hartung H-P, Calabresi PA (2005) Anti-α4 integrin therapy for multiple sclerosis: mechanisms and rationale. Neurology 64:1336–1342

    CAS  PubMed  Google Scholar 

  107. Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue EW et al (2006) Natalizumab plus interferon β1a for relapsing multiple sclerosis. N Engl J Med 354:911–923

    CAS  PubMed  Google Scholar 

  108. Ruoslahti E, Pierschbacher MD (1987) New perspectives in cell adhesion: RGD and integrins. Science 238:491–497

    CAS  PubMed  Google Scholar 

  109. Salas A, Shimaoka M, Kogan AN, Harwood C, von Andrian UH, Springer TA (2004) Rolling adhesion through an extended conformation of integrin αLβ2 and relation to α I and β I-like domain interaction. Immunity 20:393–406

    CAS  PubMed  Google Scholar 

  110. San Antonio JD, Zoeller JJ, Habursky K, Turner K, Pimtong W, Burrows M et al (2009) A key role for the integrin α2β1 in experimental and developmental angiogenesis. Am J Pathol 175:1338–1347

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Sanchez-Madrid F, Nagy J, Robbins E, Simon P, Springer T (1983) A human leukocyte differentiation antigen family with distinct alpha-subunits and a common beta-subunit: the lymphocyte function-associated antigen (LFA-1), the C3bi complement receptor (OKM1/Mac-1), and the p150,95 molecule. J Exp Med 158:1785–1803

    CAS  PubMed  Google Scholar 

  112. Sanz L, Chen R-Q, Pérez A, Hilario R, Juárez P, Marcinkiewicz C et al (2005) cDNA cloning and functional expression of jerdostatin, a novel RTS-disintegrin from trimeresurus jerdonii and a specific antagonist of the α1β1 integrin. J Biol Chem 280:40714–40722

    CAS  PubMed  Google Scholar 

  113. Schack L, Stapulionis R, Christensen B, Kofod-Olsen E, Skov Sorensen UB, Vorup-Jensen T et al (2009) Osteopontin enhances phagocytosis through a novel osteopontin receptor, the αXβ2 integrin. J Immunol 182:6943–6950

    CAS  PubMed  Google Scholar 

  114. Semba CP, Torkildsen GL, Lonsdale JD, McLaurin EB, Geffin JA, Mundorf TK et al (2012) A phase 2 randomized, double-masked, placebo-controlled study of a novel integrin antagonist (SAR 1118) for the treatment of dry eye. Am J Ophthalmol 153(1050–60):e1

    PubMed  Google Scholar 

  115. Sewald X, Gebert-Vogl B, Prassl S, Barwig I, Weiss E, Fabbri M et al (2008) Integrin subunit CD18 is the T-lymphocyte receptor for the Helicobacter pylori vacuolating cytotoxin. Cell Host Microbe 3:20–29

    CAS  PubMed  Google Scholar 

  116. Shi M, Pedchenko V, Greer BH, Van Horn WD, Santoro SA, Sanders CR et al (2012) Enhancing integrin α1 inserted (I) domain affinity to ligand potentiates integrin α1β1-mediated down-regulation of collagen synthesis. J Biol Chem 287:35139–35152

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Shimaoka M, Kim M, Cohen EH, Yang W, Astrof N, Peer D et al (2006) AL-57, a ligand-mimetic antibody to integrin LFA-1, reveals chemokine-induced affinity up-regulation in lymphocytes. Proc Natl Acad Sci U S A 103:13991–13996

    CAS  PubMed Central  PubMed  Google Scholar 

  118. Shimaoka M, Salas A, Yang W, Weitz-Schmidt G, Springer TA (2003) Small molecule integrin antagonists that bind to the β2 subunit I-like domain and activate signals in one direction and block them in the other. Immunity 19:391–402

    CAS  PubMed  Google Scholar 

  119. Shimaoka M, Springer TA (2003) Therapeutic antagonists and conformational regulation of integrin function. Nat Rev Drug Discov 2:703–716

    CAS  PubMed  Google Scholar 

  120. Shoda M, Harada T, Yano K, Stahura FL, Himeno T, Shiojiri S et al (2007) Virtual screening leads to the discovery of an effective antagonist of lymphocyte function-associated antigen-1. ChemMedChem 2:515–521

    CAS  PubMed  Google Scholar 

  121. Silva R, D’Amico G, Hodivala-Dilke KM, Reynolds LE (2008) Integrins: the keys to unlocking angiogenesis. Arterioscler Thromb Vasc Biol 28:1703–1713

    CAS  PubMed  Google Scholar 

  122. Smith-Garvin JE, Koretzky GA, Jordan MS (2009) T cell activation. Ann Rev Immunol 27:591

    CAS  Google Scholar 

  123. Springer TA, Zhu J, Xiao T (2008) Structural basis for distinctive recognition of fibrinogen γC peptide by the platelet integrin αIIbβ3. J Cell Biol 182:791–800

    CAS  PubMed Central  PubMed  Google Scholar 

  124. Staniszewska I, Walsh EM, Rothman VL, Gaathon A, Tuszynski GP, Calvete JJ et al (2009) Effect of VP12 and viperistatin on inhibition of collagen receptors: dependent melanoma metastasis. Cancer Biol Ther 8:1507–1516

    CAS  PubMed  Google Scholar 

  125. Steenhard BM, Vanacore R, Friedman D, Zelenchuk A, Stroganova L, Isom K et al (2012) Upregulated expression of integrin α1 in mesangial cells and integrin α3 and vimentin in podocytes of Col4a3-Null (Alport) mice. PLoS ONE 7:e50745

    CAS  PubMed Central  PubMed  Google Scholar 

  126. Steinman L (2005) Blocking adhesion molecules as therapy for multiple sclerosis: natalizumab. Nat Rev Drug Discovery 4:510

    CAS  Google Scholar 

  127. Stewart PL, Nemerow GR (2007) Cell integrins: commonly used receptors for diverse viral pathogens. Trends Microbiol 15:500–507

    CAS  PubMed  Google Scholar 

  128. Suchard SJ, Stetsko DK, Davis PM, Skala S, Potin D, Launay M et al (2010) An LFA-1 ({alpha}L{beta}2) small-molecule antagonist reduces inflammation and joint destruction in murine models of arthritis. J Immunol 184:3917–3926

    CAS  PubMed  Google Scholar 

  129. Tamkun J, DeSimone D, Fonda D, Patel R, Buck C, Horwitz A et al (1986) Structure of integrin, a glycoprotein involved in the transmembrane linkage between fibronectin and actin. Cell 46:271–282

    CAS  PubMed  Google Scholar 

  130. Tan CS, Koralnik IJ (2010) Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol 9:425–437

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Targan SR, Feagan BG, Fedorak RN, Lashner BA, Panaccione R, Present DH et al (2007) Natalizumab for the treatment of active Crohn’s disease: results of the ENCORE trial. Gastroenterol 132:1672–1683

    CAS  Google Scholar 

  132. The Epilog Investigators (1997) Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 336:1689–1697

    Google Scholar 

  133. The EPISTENT Investigators (1998) Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade. Evaluation of Platelet IIb/IIIa inhibitor for stenting. Lancet 352:87–92

    Google Scholar 

  134. The RESTORE Investigators (1997) Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. Circulation 96:1445–1453

    Google Scholar 

  135. Usmani N, Goodfield M (2007) Efalizumab in the treatment of discoid lupus erythematosus. Arch Dermatol 143:873–877

    CAS  PubMed  Google Scholar 

  136. Ustinov VA, Plow EF (2002) Delineation of the key amino acids involved in neutrophil inhibitory factor binding to the I-domain supports a mosaic model for the capacity of integrin αMβ2 to recognize multiple ligands. J Biol Chem 277:18769–18776

    CAS  PubMed  Google Scholar 

  137. Vaiyapuri S, Hutchinson EG, Ali MS, Dannoura A, Stanley RG, Harrison RA et al (2012) Rhinocetin, a venom-derived integrin-specific antagonist inhibits collagen-induced platelet and endothelial cell functions. J Biol Chem 287:26235–26244

    CAS  PubMed Central  PubMed  Google Scholar 

  138. Vincenti F, Mendez R, Pescovitz M, Rajagopalan PR, Wilkinson AH, Butt K et al (2007) A phase I/II randomized open-label multicenter trial of efalizumab, a humanized anti-CD11a, anti-LFA-1 in renal transplantation. Am J Transplant 7:1770–1777

    CAS  PubMed  Google Scholar 

  139. Wang Y, Kai H, Chang F, Shibata K, Tahara-Hanaoka S, S-i Honda et al (2007) A critical role of LFA-1 in the development of Th17 cells and induction of experimental autoimmune encephalomyelytis. Biochem Biophys Res Commun 353:857–862

    CAS  PubMed  Google Scholar 

  140. Wattanasin S, Kallen J, Myers S, Guo Q, Sabio M, Ehrhardt C et al (2005) 1,4-diazepane-2,5-diones as novel inhibitors of LFA-1. Bioorg Med Chem Lett 15:1217–1220

    CAS  PubMed  Google Scholar 

  141. Watterson SH, Xiao Z, Dodd DS, Tortolani DR, Vaccaro W, Potin D et al (2010) Small molecule antagonist of leukocyte function associated antigen-1 (LFA-1): structure-activity Relationships leading to the identification of 6-((5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonan-7-yl)nicotinic acid (BMS-688521). J Med Chem 53:3814–3830

    CAS  PubMed  Google Scholar 

  142. Weis SM, Stupack DG, Cheresh DA (2009) Agonizing integrin antagonists? Cancer Cell 15:359–361

    CAS  PubMed  Google Scholar 

  143. Weitz-Schmidt G, Welzenbach K, Dawson J, Kallen J (2004) Improved lymphocyte function-associated antigen-1 (LFA-1) inhibition by statin derivatives: molecular basis determined by x-ray analysis and monitoring of LFA-1 conformational changes in vitro and ex vivo. J Biol Chem 279:46764–46771

    CAS  PubMed  Google Scholar 

  144. Welzenbach K, Hommel U, Weitz-Schmidt G (2002) Small molecule inhibitors induce conformational changes in the I domain and the I-like domain of lymphocyte function-associated antigen-1. Molecular insights into integrin inhibition. J Biol Chem 277:10590–10598

    CAS  PubMed  Google Scholar 

  145. Wong K, Wo J, Ho D, Poon R, Casasnovas J, Luk J (2010) Prophylactic uses of integrin CD18-βA peptide in a murine polymicrobial peritonitis model. World J Gastroenterol 16:2648–2656

    CAS  PubMed Central  PubMed  Google Scholar 

  146. Wong KF, Luk JM, Cheng RH, Klickstein LB, and Fan S-T (2007) Characterization of two novel LPS-binding sites in leukocyte integrin bA domain. FASEB J 21: 3231–3239

    Google Scholar 

  147. Wu JP, Emeigh J, Gao DA, Goldberg DR, Kuzmich D, Miao C et al (2004) Second-generation lymphocyte function-associated antigen-1 Inhibitors: 1H-Imidazo[1,2-]imidazol-2-one derivatives. J Med Chem 47:5356–5366

    PubMed  Google Scholar 

  148. Xiao T, Takagi J, Coller BS, Wang J-H, Springer TA (2004) Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics. Nature 432:59–67

    CAS  PubMed  Google Scholar 

  149. Xie C, Zhu J, Chen X, Mi L, Nishida N, Springer TA (2010) Structure of an integrin with an αI domain, complement receptor type 4. EMBO J 29:666–679

    CAS  PubMed Central  PubMed  Google Scholar 

  150. Yang W, Carman CV, Kim M, Salas A, Shimaoka M, Springer TA (2006) A small molecule agonist of an integrin, αLβ2. J Biol Chem 281:37904–37912

    CAS  PubMed Central  PubMed  Google Scholar 

  151. Yang W, Shimaoka M, Salas A, Takagi J, Springer TA (2004) Intersubunit signal transmission in integrins by a receptor-like interaction with a pull spring. Proc Natl Acad Sci U S A 101:2906–2911

    CAS  PubMed Central  PubMed  Google Scholar 

  152. Yu L, Su Y, Paueksakon P, Cheng H, Chen X, Wang H et al (2012) Integrin [alpha]1/Akita double-knockout mice on a Balb/c background develop advanced features of human diabetic nephropathy. Kidney Int 81:1086–1097

    CAS  PubMed Central  PubMed  Google Scholar 

  153. Yuki K, Bu W, Xi J, Shimaoka M, Eckenhoff R (2013) Propofol shares the binding site with isoflurane and sevoflurane on leukocyte function-associated antigen-1. Anesth Analg 117:803–811

    CAS  PubMed  Google Scholar 

  154. Zeltz C, Orgel J, and Gullberg D (2013) Molecular composition and function of integrin-based collagen glues—introducing COLINBRIs. Biochimica et Biophysica Acta (BBA)—General Subjects (in press}

    Google Scholar 

  155. Zhang H, Astrof NS, Liu JH, Wang JH, and Shimaoka M (2009) Crystal structure of isoflurane bound to integrin LFA-1 supports a unified mechanism of volatile anesthetic action in the immune and central nervous systems. FASEB J 23(8):2735–2740

    Google Scholar 

  156. Zhong M, Gadek TR, Bui M, Shen W, Burnier J, Barr KJ et al (2012) Discovery and development of potent LFA-1/ICAM-1 antagonist SAR 1118 as an ophthalmic solution for treating dry eye. ACS Med Chem Lett 3:203–206

    CAS  PubMed Central  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, 123 St. Stephen’s Green, Dublin 2, Ireland

    Marian Brennan & Dermot Cox

Authors
  1. Marian Brennan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dermot Cox
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dermot Cox .

Editor information

Editors and Affiliations

  1. University of Bergen, Bergen, Norway

    Donald Gullberg

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Brennan, M., Cox, D. (2014). The Therapeutic Potential of I-Domain Integrins. In: Gullberg, D. (eds) I Domain Integrins. Advances in Experimental Medicine and Biology, vol 819. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-9153-3_11

Download citation

Publish with us

Policies and ethics

Search

Navigation