Tahl Zimmerman

Centro Nacional de Investigaciones Oncológicas, Madrid, Madrid, Spain

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Publications (8)39.2 Total impact

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    ABSTRACT: The integrin leukocyte function associated antigen 1 (LFA-1) binds the intercellular adhesion molecule 1 (ICAM-1) by its α(L)-chain inserted domain (I-domain). This interaction plays a key role in cancer and other diseases. We report the structure-based design, small-scale synthesis, and biological activity evaluation of a novel family of LFA-1 antagonists. The design led to the synthesis of a family of highly substituted homochiral pyrrolidines with antiproliferative and antimetastatic activity in a murine model of colon carcinoma, as well as potent antiadhesive properties in several cancer cell lines in the low micromolar range. NMR analysis of their binding to the isolated I-domain shows that they bind to the I-domain allosteric site (IDAS), the binding site of other allosteric LFA-1 inhibitors. These results provide evidence of the potential therapeutic value of a new set of LFA-1 inhibitors, whose further development is facilitated by a synthetic strategy that is versatile and fully stereocontrolled.
    Journal of Medicinal Chemistry 01/2013; · 5.61 Impact Factor
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    ABSTRACT: Conjugation of either a fluorescent dye or a drug molecule to the ε-amino groups of lysine residues of proteins has many applications in biology and medicine. However, this type of conjugation produces a heterogeneous population of protein conjugates. Because conjugation of fluorochrome or drug molecule to a protein may have deleterious effects on protein function, the identification of conjugation sites is necessary. Unfortunately, the identification process can be time-consuming and laborious; therefore, there is a need to develop a rapid and reliable way to determine the conjugation sites of the fluorescent label or drug molecule. In this study, the sites of conjugation of fluorescein-5'-isothiocyanate and rhodamine-B-isothiocyanate to free amino groups on the insert-domain (I-domain) protein derived from the α-subunit of lymphocyte function-associated antigen-1 (LFA-1) were determined by electrospray ionization quadrupole time-of-flight mass spectrometry (ESI-Q-TOF MS) along with peptide mapping using trypsin digestion. A reporter fragment of the fluorochrome moiety that is generated in the collision cell of the Q-TOF without explicit MS/MS precursor selection was used to identify the conjugation site. Selected ion plots of the reporter ion readily mark modified peptides in chromatograms of the complex digest. Interrogation of theses spectra reveals a neutral loss/precursor pair that identifies the modified peptide. The results show that one to seven fluorescein molecules or one to four rhodamine molecules were attached to the lysine residue(s) of the I-domain protein. No modifications were found in the metal ion-dependent adhesion site (MIDAS), which is an important binding region of the I-domain.
    Bioconjugate Chemistry 06/2011; 22(7):1330-6. · 4.58 Impact Factor
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    ABSTRACT: The long-term objective of this project is to utilize the I-domain protein for the α-subunit of LFA-1 to target drugs to lymphocytes by binding to ICAM receptors on the cell surface. The short-term goal is to provide proof-of-concept that I-domain conjugated to small molecules can still bind to and uptake by ICAM-1 on the surface of lymphocytes (i.e., Raji cells). To accomplish this goal, the I-domain protein was labeled with FITC at several lysine residues to produce the FITC-I-domain and CD spectroscopy showed that the FITC-I-domain has a secondary structure similar to that of the parent I-domain. The FITC-I-domain was taken up by Raji cells via receptor-mediated endocytosis and its uptake can be blocked by anti-I-domain mAb but not by its isotype control. Antibodies to ICAM-1 enhance the binding of I-domain to ICAM-1, suggesting it binds to ICAM-1 at different sites than the antibodies. The results indicate that fluorophore modification does not alter the binding and uptake properties of the I-domain protein. Thus, I-domain could be useful as a carrier of drug to target ICAM-1-expressing lymphocytes.
    Theranostics 01/2011; 1:277-89. · 7.81 Impact Factor
  • Tahl Zimmerman, Francisco J Blanco
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    ABSTRACT: Leukocyte-function associated antigen-1 (LFA-1) is an alpha(L)beta(2) chain integrin expressed on the surface of endothelial cells that modulates the behavior of leukocytes by mediating their adhesion to other cells through its interaction to cell-surface ligands. The most important ligand of LFA-1 is ICAM-1 which is expressed on the surface of endothelial cells. The interaction between LFA-1 and ICAM-1 is involved in inflammatory responses and is therefore implicated in inflammatory pathologies and autoimmune diseases; and, in addition, it is involved in many cancer processes. In light of this, there is great interest in developing small molecule, orally available, inhibitors of the LFA-1/ICAM-1 interaction. A structurally diverse collection of small molecule inhibitors has been characterized and developed either to bind the IDAS site of the alpha(L) I-domain or to the MIDAS of the beta2 I-like domain. In this review, a summary of the structure and regulation of LFA-1 will be given, followed by a description of the different classes of inhibitors that have been described to date.
    Current pharmaceutical design 02/2008; 14(22):2128-39. · 4.41 Impact Factor
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    ABSTRACT: We have used nuclear magnetic resonance to characterize the binding site of two intercellular adhesion molecule-1 derived cyclic peptides, cIBC and cIBR, to the I-domain of leukocyte function-associated antigen-1. These peptides inhibit the leukocyte function-associated antigen-1/intercellular adhesion molecule-1 interaction known to play a key role in autoimmune diseases and cancer metastasis. Perturbation of the chemical shifts and intensities of the nuclear magnetic resonance signals corresponding to a number of residues of the I-domain of leukocyte function-associated antigen-1 show that both peptides bind to the I-domain allosteric site, the binding site of I-domain allosteric inhibitors such as lovastatin, and therefore the peptides probably also act as allosteric inhibitors of leukocyte function-associated antigen-1. Molecular models of the interaction of these two cyclic peptides with leukocyte function-associated antigen-1 I-domain show that the binding mode of the three molecules are analogous: the hydrophobic residues of the peptides remain buried and occupy the same positions as the apolar groups of lovastatin, while the peptides regions containing the most polar residues are flexible and primarily exposed to the solvent. These results suggest an allosteric mechanism for the inhibitory effect on T-cell adhesion displayed by both peptides, which exhibit potential as therapeutic agents.
    Chemical Biology &amp Drug Design 11/2007; 70(4):347-53. · 2.47 Impact Factor
  • Tahl Zimmerman, Francisco J Blanco
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    ABSTRACT: There are 15 known laminins, which differ in the isoforms of the three chains that assemble into the cross-shape molecules that are observed by electron microscopy. The amino acid sequences of the rod-like portion of the long arm have long been recognized as having a potential for coiled-coil structure formation; however, an experimental determination of its structure is hampered by the complexity of laminin, a multidomain, heterotrimeric, and glycosilated 800 kDa molecule. Here, we have investigated the coiled-coil structure potential of laminin to evaluate its distribution along the long arm, the presence of conserved patterns, and differences between natural and non-natural isoforms. With these aims, we have analysed the sequences of each laminin chain in the context of the three-chain assemblies to yield an overall score of coiled-coil potential for the 15 natural laminins and for the other 30 possible but non-detected ones. The potential has been calculated with two different existing methods to exclude algorithm specific biases and with different chain alignments to evaluate the dependency of the results on uncertainties in the specific alignment along the domain. The analysis shows that the distribution of the potential is discontinuous, highly fragmented along the arm, without a common pattern except for a higher potential at the C-terminus, and that natural and non-natural laminins cannot be distinguished based on their coiled-coil potential, indicating that other factors are responsible for the selection of chain assembly.
    Journal of biomolecular Structure & Dynamics 03/2007; 24(4):413-20. · 2.98 Impact Factor
  • Angewandte Chemie International Edition 05/2005; 44(19):2903-7. · 11.34 Impact Factor
  • Angewandte Chemie 01/2005; 117(19):2963-2967.