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47 results on '"Goldfarb, Valentina"'

1. Assessing compound binding to the Eg5 motor domain using a thermal shift assay

Author

McDonnell, Patricia A., Yanchunas, Joseph, Newitt, John A., Tao, Li, Kiefer, Susan E., Ortega, Marie, Kut, Stephanie, Burford, Neil, Goldfarb, Valentina, Duke, Gerald J., Shen, Henry, Metzler, William, Doyle, Michael, Chen, Zhong, Tarby, Christine, Borzilleri, Robert, Vaccaro, Wayne, Gottardis, Marco, Lu, Songfeng, Crews, Donald, Kim, Kyoung, Lombardo, Louis, and Roussell, Deborah L.

Published
2009
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3. Backbone and side chain dynamics of uncomplexed human adipocyte and muscle fatty acid-binding proteins

Author

Constantine, Keith L., Friedrichs, Mark S., Wittekind, Michael, Jamil, Haris, Chu, Ching-Hsuen, Parker, Rex A., Goldfarb, Valentina, Mueller, Luciano, and Farmer, Bennett T., II

Subjects
Carrier proteins -- Analysis, Fat cells -- Genetic aspects, Fatty acids -- Genetic aspects, Biological sciences, Chemistry
Abstract

A study on the backbone and side chain mechanisms of uncomplexed human adipocyte lipid-binding protein (apo-A-LBP) and muscle fatty acid-binding proteins (apo-M-FABP) is presented. A-LBPs and M-FABPs are intracellular lipid-binding proteins that transport and store lipids. A-LBPs are found in fat cells while M-FABPs are found in skeletal muscles, the heart and the kidneys. These proteins have the same fold structure made up of 10 antiparallel beta strands and a helix-loop-helix design joining the A and B beta strands.

Published
1998

6. Orientation of peptide fragments from Sos protein bound to the N-terminal SH3 domain of Grb2 determined by NMR spectroscopy

Author

Wittekind, Michael, Mapelli, Claudio, Farmer, Bennett T. II, Suen, Ki-Ling, Goldfarb, Valentina, Tsao, Jonglin, Lavoie, Thomas, Barbacid, Mariano, Meyers, Chester A., and Mueller, Luciano

Subjects
Peptides -- Research, Protein binding -- Analysis, Binding sites (Biochemistry) -- Analysis, Biological sciences, Chemistry
Abstract

NMR spectroscopic analyses of the protein-protein interactions between the mouse Sos-2 (mSos-2) protein and the mouse Grb2 (mGrb-2) N-terminal SH3 domain which forms a complex with a 15-residue peptide reveal that the orientation of the Sos-A peptides bound to the Grb2 SH3 domain is the opposite of the orientation of RLP1 peptides bound to PI3K SH3 domain. The basic residue at position 10 of the Sos-A peptide optimizes the binding process. Large variations in the amide chemical shifts are seen in the peptide-binding site of the SH3 domain after the binding. A mSos peptide relating to 1152-1161 residues displays a 10-fold higher binding to Grb2 N-terminal SH3 domain than the Sos-A peptide.

Published
1994

7. Sequential 1H and 15N NMR assignments and secondary structure of a recombinant anti-digoxin antibody V(sub L) domain

Author

Constantine, Keith L., Goldfarb, Valentina, Wittekind, Michael, Anthony, James, Shi-Chung Ng, and Mueller, Luciano

Subjects
Immunoglobulin G -- Physiological aspects, Magnetic resonance imaging -- Usage, Biological sciences, Chemistry
Abstract

A study was done on the secondary structure of a recombinant anti-digoxin antibody V(sub L) domain using heteronuclear two-dimensional and three-dimensional magnetic resonance imaging spectroscopy. The V(sub L) domain was shown to be a nine-stranded anti-parallel beta-barrel secondary structure with locations of slowly exchanging amide protons. It was also shown that the V(sub L) domain in solution and that which is part of the crystalline 26-10 Fab-digoxin complex possess the same characteristics.

Published
1992

10. Design, synthesis, functional and structural characterization of an inhibitor of N-acetylneuraminate-9-phosphate phosphatase: Observation of extensive dynamics in an enzyme/inhibitor complex

Author

Kim, Soong-Hoon, Constantine, Keith L., Duke, Gerald J., Goldfarb, Valentina, Hunt, John T., Johnson, Stephen, Kish, Kevin, Klei, Herbert E., McDonnell, Patricia A., Metzler, William J., Mueller, Luciano, Poss, Michael A., Fairchild, Craig R., and Bhide, Rajeev S.

Published
2013
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12. Incorporation of 1H/13C/15N-(Ile, Leu, Val) into a perdeuterated, 15N-labeled protein: potential in structure determination of large proteins by NMR

Author

Metzler, William J., Wittekind, Michael, Goldfarb, Valentina, Mueller, Luciano, and Farmer, Bennett T., II

Subjects
Nuclear magnetic resonance spectroscopy -- Usage, Proteins -- Structure, Chemistry
Abstract

ILV residues were used as the 1H/13C-labeled specific residues for determining protein structure by NMR spectroscopy. Structural data derived from 1HN-1HN NOEs must be uniquely complemented by those derived from NOEs between ILV side chain protons. The well-characterized murin Grb2 N-SH3/SOSE protein-peptide complex was utilized to illustrate the specificity of this labeling method.

Published
1996

13. Small Molecule Receptor Protein Tyrosine Phosphatase γ (RPTPγ) Ligands That Inhibit Phosphatase Activity via Perturbation of the Tryptophan–Proline–Aspartate (WPD) Loop

Author

Sheriff, Steven, primary, Beno, Brett R., additional, Zhai, Weixu, additional, Kostich, Walter A., additional, McDonnell, Patricia A., additional, Kish, Kevin, additional, Goldfarb, Valentina, additional, Gao, Mian, additional, Kiefer, Susan E., additional, Yanchunas, Joseph, additional, Huang, Yanling, additional, Shi, Shuhao, additional, Zhu, Shirong, additional, Dzierba, Carolyn, additional, Bronson, Joanne, additional, Macor, John E., additional, Appiah, Kingsley K., additional, Westphal, Ryan S., additional, O’Connell, Jonathan, additional, and Gerritz, Samuel W., additional

Published
2011
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14. Cloning, purification, crystallization and preliminary X-ray analysis of the catalytic domain of human receptor-like protein tyrosine phosphatase γ in three different crystal forms

Author

Kish, Kevin, primary, McDonnell, Patricia A., additional, Goldfarb, Valentina, additional, Gao, Mian, additional, Metzler, William J., additional, Langley, David R., additional, Bryson, James W., additional, Kiefer, Susan E., additional, Carpenter, Brian, additional, Kostich, Walter A., additional, Westphal, Ryan S., additional, and Sheriff, Steven, additional

Published
2011
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15. Structural and functional characterization of CFE88: Evidence that a conserved and essential bacterial protein is a methyltransferase

Author

Constantine, Keith L., primary, Krystek, Stanley R., additional, Healy, Matthew D., additional, Doyle, Michael L., additional, Siemers, Nathan O., additional, Thanassi, Jane, additional, Yan, Ning, additional, Xie, Dianlin, additional, Goldfarb, Valentina, additional, Yanchunas, Joseph, additional, Tao, Li, additional, Dougherty, Brian A., additional, and Farmer, Bennett T., additional

Published
2009
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16. Multiple and Single Binding Modes of Fragment-Like Kinase Inhibitors Revealed by Molecular Modeling, Residue Type-Selective Protonation, and Nuclear Overhauser Effects

Author

Constantine, Keith L., primary, Mueller, Luciano, additional, Metzler, William J., additional, McDonnell, Patricia A., additional, Todderud, Gordon, additional, Goldfarb, Valentina, additional, Fan, Yi, additional, Newitt, John A., additional, Kiefer, Susan E., additional, Gao, Mian, additional, Tortolani, David, additional, Vaccaro, Wayne, additional, and Tokarski, John, additional

Published
2008
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18. 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 of Leukocyte Function Associated Antigen-1

Author

Potin, Dominique, primary, Launay, Michele, additional, Monatlik, Francoise, additional, Malabre, Patrice, additional, Fabreguettes, Maud, additional, Fouquet, Andre, additional, Maillet, Magali, additional, Nicolai, Eric, additional, Dorgeret, Loïc, additional, Chevallier, François, additional, Besse, Dominique, additional, Dufort, Monique, additional, Caussade, François, additional, Ahmad, Syed Z., additional, Stetsko, Dawn K., additional, Skala, Stacey, additional, Davis, Patricia M., additional, Balimane, Praveen, additional, Patel, Karishma, additional, Yang, Zheng, additional, Marathe, Punit, additional, Postelneck, Jennifer, additional, Townsend, Robert M., additional, Goldfarb, Valentina, additional, Sheriff, Steven, additional, Einspahr, Howard, additional, Kish, Kevin, additional, Malley, Mary F., additional, DiMarco, John D., additional, Gougoutas, Jack Z., additional, Kadiyala, Pathanjali, additional, Cheney, Daniel L., additional, Tejwani, Ravindra W., additional, Murphy, Denette K., additional, Mcintyre, Kim W., additional, Yang, Xiaoxia, additional, Chao, Sam, additional, Leith, Leslie, additional, Xiao, Zili, additional, Mathur, Arvind, additional, Chen, Bang-Chi, additional, Wu, Daugh-Rurng, additional, Traeger, Sarah C., additional, McKinnon, Murray, additional, Barrish, Joel C., additional, Robl, Jeffrey A., additional, Iwanowicz, Edwin J., additional, Suchard, Suzanne J., additional, and Dhar, T. G. Murali, additional

Published
2006
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19. NMR Structure of a Potent Small Molecule Inhibitor Bound to Human Keratinocyte Fatty Acid-Binding Protein

Author

McDonnell, Patricia A., primary, Constantine, Keith L., additional, Goldfarb, Valentina, additional, Johnson, Stephen R., additional, Sulsky, Richard, additional, Magnin, David R., additional, Robl, Jeffrey A., additional, Caulfield, Thomas J., additional, Parker, Rex A., additional, Taylor, David S., additional, Adam, Leonard P., additional, Metzler, William J., additional, Mueller, Luciano, additional, and Farmer, Bennett T., additional

Published
2006
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26. Small Molecule Receptor Protein Tyrosine Phosphatase γ (RPTPγ) Ligands That Inhibit Phosphatase Activity via Perturbation of the Tryptophan–Proline–Aspartate (WPD) Loop.

Author

Sheriff, Steven, Beno, Brett R., Zhai, Weixu, Kostich, Walter A., McDonnell, Patricia A., Kish, Kevin, Goldfarb, Valentina, Gao, Mian, Kiefer, Susan E., Yanchunas, Joseph, Huang, Yanling, Shi, Shuhao, Zhu, Shirong, Dzierba, Carolyn, Bronson, Joanne, Macor, John E., Appiah, Kingsley K., Westphal, Ryan S., O’Connell, Jonathan, and Gerritz, Samuel W.

Published
2011
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27. Synthesis and secretion of hemopexin in primary cultures of rat hepatocytes Demonstration of an intracellular precursor of hemopexin.

Author

Katz, Norbert R., Goldfarb, Valentina, Liem, Heng, and Muller-Eberhard, Ursula

Subjects
*IRON in the body, *LIVER cells, *GLYCOSYLATION, *TUNICAMYCIN, *PROTEINS, *SECRETION
Abstract

Secretion of hemopexin (20% carbohydrate) and its dependence on glycosylation was studied in primary rat hepatocyte cultures in comparison to the secretion of transferrin (5% carbohydrate). 1. In pulse-chase experiments with [35S]methionine half of the labeled hemopexin was secreted in 30 min. By contrast, it took approximately 50 min for secretion of half of the transferrin. 2. Tunicamycin treatment of cultures significantly delayed the secretion of hemopexin but not that of transferrin. 3. During the pulse period a prominent intracellular precursor of hemopexin, smaller than the mature protein, was evident. It is concluded that the extent of glycosylation of a secretory protein is not necessarily a determinant of the transit time required for intracellular processing and secretion. In the case of hemopexin the glycosylation apparently facilitates the secretion although it is not an absolute prerequisite for the exocytosis of this protein. [ABSTRACT FROM AUTHOR]

Published
1985
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28. Isolation and Characterization of a Lipid-Embedded Domain of the Acetylcholine Receptor from <em>Torpedo californica</em>.

Author

Tarrab-Hazdai, Rebeca and Goldfarb, Valentina

Subjects
*ACETYLCHOLINE, *NEUROTRANSMITTERS, *CHOLINE, *CHROMATOGRAPHIC analysis, *COLLOIDS, *PHASE partition
Abstract

A lipid-embedded domain of the acetylcholine receptor isolated from acetylcholine-rich membrane fragments from the electric organ of Torpedo californica and identified by photolabeling with the lipid-soluble reagent 5-[125I]iodonaphthyl-1-azide was purified by affinity chromatography and characterized. Four subunits of apparent Mr 40000, 48000, 55000, and 64000 were found after sodium dodecyl sulfate/polyacrylamide gel electrophoresis of the purified material. Exhaustive trypsinization of the purified acetylcholine receptor yielded two domains: an unlabeled 27000-Mr segment and labeled 13000-Mr lipid-embedded polypeptide(s) which were separable by rechromatography with Sepharose-bound Naja naja siamensis neurotoxin. Trypsin was separated from the 13000-dalton polypeptide(s) by gel filtration on CMC-Sephadex G-50 or by affinity chromatography with Sepharose-bound soybean trypsin inhibitor. The 13000-dalton fragment behaved as a proteolipid upon butanol extraction and ether precipitation. The ether precipitate, which had a relatively hydrophobic amino acid composition resembling the original protein, yielded only one labeled polypeptide band upon electrophoresis. Immunological studies showed that the lipid-embedded domain of the acetylcholine receptor was strongly bound to anti-(denatured receptor) antibodies which are essentially directed against sequential antigenic determinants. Furthermore, antibodies made in rabbits against this lipid-embedded domain recognized the membrane-bound receptor, the detergent (Triton X-100)-isolated receptor, and the modified receptor. The availability of this purified lipid-embedded segment of the acetylcholine receptor permits both the determination of its sequence and the study of the cross-reactivity of anti-bodies specific for this domain with other ionophoric proteins. [ABSTRACT FROM AUTHOR]

Published
1982
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32. Discovery and Development of 5-(5S,9R)-9- (4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1- methyl-2,4-dioxo-1,3,7-triazaspiro4.4non- 7-yl-methyl-3-thiophenecarboxylic acid (BMS-587101)A Small Molecule Antagonist Leukocyte Function Associated Antigen-1

Author

Potin, Dominique, Launay, Michele, Monatlik, Francoise, Malabre, Patrice, Fabreguettes, Maud, Fouquet, Andre, Maillet, Magali, Nicolai, Eric, Dorgeret, Loïc, Chevallier, François, Besse, Dominique, Dufort, Monique, Caussade, François, Z. Ahmad, Syed, K. Stetsko, Dawn, Skala, Stacey, M. Davis, Patricia, Balimane, Praveen, Patel, Karishma, Yang, Zheng, Marathe, Punit, Postelneck, Jennifer, M. Townsend, Robert, Goldfarb, Valentina, Sheriff, Steven, Einspahr, Howard, Kish, Kevin, F. Malley, Mary, D. DiMarco, John, Z. Gougoutas, Jack, Kadiyala, Pathanjali, L. Cheney, Daniel, W. Tejwani, Ravindra, K. Murphy, Denette, W. Mcintyre, Kim, Yang, Xiaoxia, Chao, Sam, Leith, Leslie, Xiao, Zili, Mathur, Arvind, Chen, Bang-Chi, Wu, Daugh-Rurng, C. Traeger, Sarah, McKinnon, Murray, C. Barrish, Joel, A. Robl, Jeffrey, J. Iwanowicz, Edwin, J. Suchard, Suzanne, and G. Murali Dhar, T.

Abstract

LFA-1 (leukocyte function-associated antigen-1), is a member of the 2-integrin family and is expressed on all leukocytes. This letter describes the discovery and preliminary SAR of spirocyclic hydantoin based LFA-1 antagonists that culminated in the identification of analog 8as a clinical candidate. We also report the first example of the efficacy of a small molecule LFA-1 antagonist in combination with CTLA-4Ig in an animal model of transplant rejection.

Published
2006
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33. NMR Structure of a Potent Small Molecule Inhibitor Bound to Human Keratinocyte Fatty Acid-Binding Protein

Author

A. McDonnell, Patricia, L. Constantine, Keith, Goldfarb, Valentina, R. Johnson, Stephen, Sulsky, Richard, R. Magnin, David, A. Robl, Jeffrey, J. Caulfield, Thomas, A. Parker, Rex, S. Taylor, David, P. Adam, Leonard, J. Metzler, William, Mueller, Luciano, and T. Farmer, Bennett

Abstract

The NMR structure is presented for compound 1(BMS-480404) (Ki 33 (±2) nM) bound to keratinocyte fatty acid-binding protein. This article describes interactions between a high affinity drug-like compound and a member of the fatty acid-binding protein family. A benzyl group ortho to the mandelic acid in 1occupies an area of the protein that fatty acids do not normally contact. Similar to that in the kFABP−palmitic acid structure, the acid moiety in 1is proximal to R129 and Y131. Computational modeling indicates that the acid moiety in 1interacts indirectly via a modeled water molecule to R109.

Published
2006
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34. Partial characterization of intra- and extracellular forms of the glycoprotein hemopexin in liver cell culture and cell-free translation

Author

Katz, Norbert R., Giffhorn, Susanne, Goldfarb, Valentina, and Muller-Eberhard, Ursula

Abstract

Primary cultures of rat hepatocytes produce extracellular and intracellular species of hemopexin. We examined the presence of high-mannose oligosaccharides and neuraminic acid residues in these species by comparing their electrophoretic mobility on SDS-PAGE before and after digestion by endoglycosidase H and neuraminidase. The predominant intracellular form was not susceptible to digestion by neuraminidase but was sensitive to endoglycosidase treatment, which digested it to a species with a molecular weight comparable to that of the sole hemopexin species produced by tunicamycin-treated hepatocytes and that produced by invitrotranslation. By contrast, both the minor intracellular and the extracellular species of hemopexin were neuraminidase-, yet not endoglycosidase H-sensitive, and may be identical. It can be concluded that the intracellular precursor contains high-mannose type oligosaccharides which are processed to complex type oligosaccharides shortly before secretion of hemopexin.

Published
1985
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35. Production and Characterization of an Antibody Fv Fragment <SUP>15</SUP>N-Labeled in the V<SUB>L</SUB> Domain Only

Author

Goldfarb, Valentina, Wittekind, Michael, Jeffrey, Philip D., Mueller, Luciano, and Constantine, Keith L.

Abstract

Procedures for separating and recombining the light-chain variable (VL) and heavy-chain variable (VH) domains of antibody Fv fragments have been applied to produce a recombinant Fv of the anti-digoxin antibody 26-10 that is 15N-labeled exclusively in the VL domain. Comparison of a two-dimensional 1H-15N heteronuclear single-quantum correlation (HSQC) spectrum of the reconstituted Fv with a HSQC spectrum of a fully 15N-labeled Fv sample reveals that all 1H-15N correlations of the VL domain align precisely in both spectra. Assignments for 105 of the 106 backbone HN groups of the VL domain within the reconstituted Fv have been obtained by analysis of three-dimensional nuclear Overhauser effect spectroscopy-HSCQ and total correlation spectroscopy-HSQC spectra with reference to assignments previously reported for the isolated VL domain. Chemical shift differences between the isolated VL domain and the VL domain within the Fv are moderately correlated with proximity to the surfaces of the VH domain and bound hapten (ouabain) as defined by X-ray crystallography and molecular modeling. These results demonstrate that nuclear magnetic resonance studies of reconstituted antibody Fv fragments, in conjunction with investigations of isolated antibody domains, can yield extensive resonance assignments for the Fv. This will facilitate detailed studies of antigen-antibody and domain-domain interactions. Copyright 1993, 1999 Academic Press

Published
1993
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36. Aliphatic 1H and 13C resonance assignments for the 26-10 antibody VL domain derived from heteronuclear multidimensional NMR spectroscopy

Author

Constantine, Keith L., Goldfarb, Valentina, Wittekind, Michael, Friedrichs, Mark S., Anthony, James, Ng, Shi-Chung, and Mueller, Luciano

Abstract

Extensive 1H and 13C assignments have been obtained for the aliphatic resonances of a uniformly 13C-and 15N-labeled recombinant VL domain from the anti-digoxin antibody 26-10. Four-dimensional triple resonance NMR data acquired with the HNCAHA and HN(CO)CAHA pulse sequences [Kay et al. (1992) J. Magn. Reson., 98, 443–450] afforded assignments for the backbone HN, N, Ha and Ca resonances. These data confirm and extend HN, N and Ha assignments derived previously from three-dimensional 1H-15N NMR studies of uniformly 15N-labeled VL domain [Constantine et al. (1992), Biochemistry, 31, 5033–5043]. The identified Ha and Ca resonances provided a starting point for assigning the side-chain aliphatic 1H and 13C resonances using three-dimensional HCCH-COSY and HCCH-TOCSY experiments [Clore et al. (1990), Biochemistry, 29, 8172–8184]. The Ca and Cß chemical shifts are correlated with the VL domain secondary structure. The extensive set of side-chain assignments obtained will allow a detailed comparison to be made between the solution structure of the isolated VL domain and the X-ray structure of the VL domain within the 26–10 Fab.

Published
1993
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44. Phosphate Relations of Acetabularia: Phosphate Pools, Adenylate Phosphates and 32P Influx Kinetics

Author

GOLDFARB, VALENTINA, SANDERS, DALE, and GRADMANN, DIETRICH

Abstract

Steady state phosphate relations are determined for the marine alga Acetabularia mediterranea with respect to cellular phosphate pools and phosphate transport. About 20% of the cellular acid-labile phosphate is found in the cell wall fraction (low speed sediment). By the use of cytoplasm-depleted cell segments, it isa established that only about 10% of the total intracellular phosphate is localized in the vacuole when cells are bathed in normal phosphate concentration (<30 μM). Measurements of ATP, ADP, AMP and inorganic phosphate (Pj) in the entire cytoplasm and in isolated chloroplasts has enabled the calculation of the cytosolic adenylate energy charge (0.7–0.9) and phosphate potential (110−170 mV). Influx of 32P, displays complex kinetics. Four components for uptake (approximate time constants: (A) 1 s, (B) 20 s, (C) 300 s and (D) 3000 s) are tentatively identified. Focusing on the faster components, B and C, and possibly even A, appear to be metabolically-linked, as judged by their sensitivity to temperature and to the inhibitor 2, 4-dinitrophenol. These three components of influx are proportional to the external P, concentration for values <30 μM, but B and C tend to saturate at higher concentrations. The results are discussed with respect to the energetics of transport at the plasmalemma of Acetabularia, especially the activity of the electrogenic CI-ATPase.

Published
1984
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45. Reversal of Electrogenic Cl- Pump in Acetabularia Increases Level and 32P Labelling of ATP

Author

GOLDFARB, VALENTINA, SANDERS, DALE, and GRADMANN, DIETRICH

Abstract

In order to test the prediction that the Cl− ATPase in the plasmalemma of Acetabularia is reversible, the content and 32P labelling of ATP in centrifuged, cytoplasm-depleted stalk segments has been measured upon incubation in 32P containing media with normal (c. 500 mM) and zero Cl−concentration. Increases in content and labelling of ATP could be demonstrated when the preparations were exposed to zero external Cl− (1.1 M sorbitol, isotonic with the control medium–emdash Erdschreiber solution). These effects are reduced in 1: 1 mixtures of 1.1 M sorbitol with 0.55 M Nal or Na-benzenesulphonate, the latter two of which are known to diminish the number of active Cl− pumps. Increased ATP content upon exposure to sorbitol is not observed at 5 °C, when the Cl- pump is known to be strongly inhibited. These results provide strong evidence for the hypothesis that the electrogenic Cl− pump is a reversible, primary Cl− transporting ATPase. The relationship of these results to the transmembrane potential difference measured under the same conditions is not yet clear.

Published
1984
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47. 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 of leukocyte function associated antigen-1.

Author

Potin D, Launay M, Monatlik F, Malabre P, Fabreguettes M, Fouquet A, Maillet M, Nicolai E, Dorgeret L, Chevallier F, Besse D, Dufort M, Caussade F, Ahmad SZ, Stetsko DK, Skala S, Davis PM, Balimane P, Patel K, Yang Z, Marathe P, Postelneck J, Townsend RM, Goldfarb V, Sheriff S, Einspahr H, Kish K, Malley MF, DiMarco JD, Gougoutas JZ, Kadiyala P, Cheney DL, Tejwani RW, Murphy DK, Mcintyre KW, Yang X, Chao S, Leith L, Xiao Z, Mathur A, Chen BC, Wu DR, Traeger SC, McKinnon M, Barrish JC, Robl JA, Iwanowicz EJ, Suchard SJ, and Dhar TG

Subjects
Animals, Cell Adhesion drug effects, Crystallography, X-Ray, Dogs, Graft Rejection prevention & control, Humans, Lymphocyte Function-Associated Antigen-1 chemistry, Mice, Models, Molecular, Molecular Structure, Pneumonia drug therapy, Pneumonia immunology, Spiro Compounds pharmacokinetics, Spiro Compounds pharmacology, Stereoisomerism, Structure-Activity Relationship, Thiophenes pharmacokinetics, Thiophenes pharmacology, Transplantation, Homologous, Lymphocyte Function-Associated Antigen-1 metabolism, Spiro Compounds chemical synthesis, Thiophenes chemical synthesis
Abstract

LFA-1 (leukocyte function-associated antigen-1), is a member of the beta2-integrin family and is expressed on all leukocytes. This letter describes the discovery and preliminary SAR of spirocyclic hydantoin based LFA-1 antagonists that culminated in the identification of analog 8 as a clinical candidate. We also report the first example of the efficacy of a small molecule LFA-1 antagonist in combination with CTLA-4Ig in an animal model of transplant rejection.

Published
2006
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