{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T17:13:52Z","timestamp":1791134032552,"version":"4.1.0"},"reference-count":30,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"5557","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Science"],"published-print":{"date-parts":[[2002,2,8]]},"abstract":"<jats:p>The protein-protein interaction between leukocyte functional antigen\u20131 (LFA-1) and intercellular adhesion molecule\u20131 (ICAM-1) is critical to lymphocyte and immune system function. Here, we report on the transfer of the contiguous, nonlinear epitope of ICAM-1, responsible for its association with LFA-1, to a small-molecule framework. These LFA-1 antagonists bound LFA-1, blocked binding of ICAM-1, and inhibited a mixed lymphocyte reaction (MLR) with potency significantly greater than that of cyclosporine A. Furthermore, in comparison to an antibody to LFA-1, they exhibited significant anti-inflammatory effects in vivo. These results demonstrate the utility of small-molecule mimics of nonlinear protein epitopes and the protein epitopes themselves as leads in the identification of novel pharmaceutical agents.<\/jats:p>","DOI":"10.1126\/science.295.5557.1086","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T05:35:18Z","timestamp":1027748118000},"page":"1086-1089","source":"Crossref","is-referenced-by-count":147,"title":["Generation of an LFA-1 Antagonist by the Transfer of the ICAM-1 Immunoregulatory Epitope to a Small Molecule"],"prefix":"10.1126","volume":"295","author":[{"given":"T. R.","family":"Gadek","sequence":"first","affiliation":[{"name":"Departments of 1Bioorganic Chemistry,2Immunology, 3Protein Engineering,4Pathology, 5Small Molecule Pharmacology, and7Antibody Technology, Genentech, One DNA Way, South San Francisco, CA 94080, USA. 6Roche Research Center, Hoffmann\u2013La Roche, Nutley, NJ 07110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. J.","family":"Burdick","sequence":"additional","affiliation":[{"name":"Departments of 1Bioorganic Chemistry,2Immunology, 3Protein Engineering,4Pathology, 5Small Molecule Pharmacology, and7Antibody Technology, Genentech, One DNA Way, South San Francisco, CA 94080, USA. 6Roche Research Center, Hoffmann\u2013La Roche, Nutley, NJ 07110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. S.","family":"McDowell","sequence":"additional","affiliation":[{"name":"Departments of 1Bioorganic Chemistry,2Immunology, 3Protein Engineering,4Pathology, 5Small Molecule Pharmacology, and7Antibody Technology, Genentech, One DNA Way, South San Francisco, CA 94080, USA. 6Roche Research Center, Hoffmann\u2013La Roche, Nutley, NJ 07110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. S.","family":"Stanley","sequence":"additional","affiliation":[{"name":"Departments of 1Bioorganic Chemistry,2Immunology, 3Protein Engineering,4Pathology, 5Small Molecule Pharmacology, and7Antibody Technology, Genentech, One DNA Way, South San Francisco, CA 94080, USA. 6Roche Research Center, Hoffmann\u2013La Roche, Nutley, NJ 07110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"J. C.","family":"Marsters","sequence":"additional","affiliation":[{"name":"Departments of 1Bioorganic Chemistry,2Immunology, 3Protein Engineering,4Pathology, 5Small Molecule Pharmacology, and7Antibody Technology, Genentech, One DNA Way, South San Francisco, CA 94080, USA. 6Roche Research Center, Hoffmann\u2013La Roche, Nutley, NJ 07110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. J.","family":"Paris","sequence":"additional","affiliation":[{"name":"Departments of 1Bioorganic Chemistry,2Immunology, 3Protein Engineering,4Pathology, 5Small Molecule Pharmacology, and7Antibody Technology, Genentech, One DNA Way, South San Francisco, CA 94080, USA. 6Roche Research Center, Hoffmann\u2013La Roche, Nutley, NJ 07110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. 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A.","family":"Zioncheck","sequence":"additional","affiliation":[{"name":"Departments of 1Bioorganic Chemistry,2Immunology, 3Protein Engineering,4Pathology, 5Small Molecule Pharmacology, and7Antibody Technology, Genentech, One DNA Way, South San Francisco, CA 94080, USA. 6Roche Research Center, Hoffmann\u2013La Roche, Nutley, NJ 07110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. P.","family":"Lee","sequence":"additional","affiliation":[{"name":"Departments of 1Bioorganic Chemistry,2Immunology, 3Protein Engineering,4Pathology, 5Small Molecule Pharmacology, and7Antibody Technology, Genentech, One DNA Way, South San Francisco, CA 94080, USA. 6Roche Research Center, Hoffmann\u2013La Roche, Nutley, NJ 07110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Gribling","sequence":"additional","affiliation":[{"name":"Departments of 1Bioorganic Chemistry,2Immunology, 3Protein Engineering,4Pathology, 5Small Molecule Pharmacology, and7Antibody Technology, Genentech, One DNA Way, South San Francisco, CA 94080, USA. 6Roche Research Center, Hoffmann\u2013La Roche, Nutley, NJ 07110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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M.","family":"Keating","sequence":"additional","affiliation":[{"name":"Departments of 1Bioorganic Chemistry,2Immunology, 3Protein Engineering,4Pathology, 5Small Molecule Pharmacology, and7Antibody Technology, Genentech, One DNA Way, South San Francisco, CA 94080, USA. 6Roche Research Center, Hoffmann\u2013La Roche, Nutley, NJ 07110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. H.","family":"Beresini","sequence":"additional","affiliation":[{"name":"Departments of 1Bioorganic Chemistry,2Immunology, 3Protein Engineering,4Pathology, 5Small Molecule Pharmacology, and7Antibody Technology, Genentech, One DNA Way, South San Francisco, CA 94080, USA. 6Roche Research Center, Hoffmann\u2013La Roche, Nutley, NJ 07110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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C.","family":"Bodary","sequence":"additional","affiliation":[{"name":"Departments of 1Bioorganic Chemistry,2Immunology, 3Protein Engineering,4Pathology, 5Small Molecule Pharmacology, and7Antibody Technology, Genentech, One DNA Way, South San Francisco, CA 94080, USA. 6Roche Research Center, Hoffmann\u2013La Roche, Nutley, NJ 07110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0049-0172(96)80034-5"},{"key":"e_1_3_1_3_2","unstructured":"J. H. Spragg in Molecular Biology of Cell Adhesion Molecules M. A. Horton Ed. (Wiley New York 1996) chap. 8 pp. 131\u2013154."},{"key":"e_1_3_1_4_2","doi-asserted-by":"publisher","DOI":"10.1006\/clin.1996.0069"},{"key":"e_1_3_1_5_2","doi-asserted-by":"publisher","DOI":"10.1006\/clin.1994.1130"},{"key":"e_1_3_1_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/0008-8749(92)90294-Y"},{"key":"e_1_3_1_7_2","first-page":"412","volume":"55","author":"Nakakura E. K.","year":"1993","unstructured":"Nakakura E. K., et al., Transplantation 55, 412 (1993).","journal-title":"Transplantation"},{"key":"e_1_3_1_8_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.157.11.4986"},{"key":"e_1_3_1_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0190-9622(00)90214-7"},{"key":"e_1_3_1_10_2","unstructured":"H. Granlund in Curr. Opin. Anti-Inflammatory Immunomodulatory Invest. Drugs 2 332 (2000)."},{"key":"e_1_3_1_11_2","unstructured":"Single-letter abbreviations for the amino acid residues are as follows: A Ala; C Cys; D Asp; E Glu; F Phe; G Gly; H His; I Ile; K Lys; L Leu; M Met; N Asn; P Pro; Q Gln; R Arg; S Ser; T Thr; V Val; W Trp; and Y Tyr. X indicates any residue."},{"key":"e_1_3_1_12_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.8.3.501"},{"key":"e_1_3_1_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.8.4134"},{"key":"e_1_3_1_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(90)90805-O"},{"key":"e_1_3_1_15_2","unstructured":"Supplementary material is available at Science Online at www.sciencemag.org\/cgi\/content\/full\/295\/5557\/1086\/DC1"},{"key":"e_1_3_1_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.7.2471"},{"key":"e_1_3_1_17_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00052a036"},{"key":"e_1_3_1_18_2","unstructured":"S. C. Bodary P. Gribling W. P. Lee unpublished data."},{"key":"e_1_3_1_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.340150308"},{"key":"e_1_3_1_20_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja00091a007"},{"key":"e_1_3_1_21_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja00050a001"},{"key":"e_1_3_1_22_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja00091a008"},{"key":"e_1_3_1_23_2","unstructured":"D. J. Burdick in PCT Int. Appl. (Genentech USA). WO 9949856 (1999) p. 9."},{"key":"e_1_3_1_24_2","unstructured":"Experimental methods for an LFA-1 ELISA assay (p. 65) the mixed lymphocyte reaction (MLR) (p. 67) and the synthesis of compounds 2 through 4 (p. 68) are found in D. J. Burdick PCT Int. Appl. (Genentech USA). WO 9949856 (1999)."},{"key":"e_1_3_1_25_2","unstructured":"In the course of the studies presented here several reports appeared describing small molecule antagonists of LFA-1\/ICAM (25\u201327). Two have identified compounds which interact with LFA-1's allosteric I domain site (26 27). Preliminary studies with compound 4 indicate that it binds at a different site on LFA-1 and that the allosteric site antagonist(s) do not inhibit the binding of compound 4 to LFA-1."},{"key":"e_1_3_1_26_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.163.10.5173"},{"key":"e_1_3_1_27_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1999.3047"},{"key":"e_1_3_1_28_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm000503f"},{"key":"e_1_3_1_29_2","doi-asserted-by":"publisher","DOI":"10.1517\/13543776.11.9.1383"},{"key":"e_1_3_1_30_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.8.4140"},{"key":"e_1_3_1_31_2","unstructured":"We thank P. Barker C. Quan J. Tom and M. Struble for help with peptide synthesis and compound purification S. Spencer for protein preparation and purification and J. Burnier R. Lazarus and R. G. Hammonds for helpful discussions in the preparation of the manuscript."}],"container-title":["Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/science.295.5557.1086","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,13]],"date-time":"2024-01-13T04:56:26Z","timestamp":1705121786000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/science.295.5557.1086"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2002,2,8]]},"references-count":30,"journal-issue":{"issue":"5557","published-print":{"date-parts":[[2002,2,8]]}},"alternative-id":["10.1126\/science.295.5557.1086"],"URL":"https:\/\/doi.org\/10.1126\/science.295.5557.1086","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.1002376.48304","asserted-by":"object"},{"id-type":"doi","id":"10.3410\/f.1002376.47704","asserted-by":"object"}]},"ISSN":["0036-8075","1095-9203"],"issn-type":[{"value":"0036-8075","type":"print"},{"value":"1095-9203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2002,2,8]]}}}