Research In the Lab

Cell surface receptors mediate the transfer of information between cells and their environment. As a result, receptors play vital roles in all aspects of cell biology including development, immune response, homeostasis, and pharmacology. Although many receptor systems have been intensely studied, fundamental questions about their molecular function remain unanswered. Research in our group applies chemical biology to improve our mechanistic understanding of membrane biology.

Specific areas of research include:

Inhibitors for membrane enzymes (Neuraminidases)

Glycolipids are a critical structural component of the plasma membrane. In addition to biosynthetic pathways, glycolipid content is regulated by glycosyl hydrolases that modify these molecules while in the membrane environment. Our group has been investigating the role of the membrane-associated neuraminidases (NEU1, NEU3, and NEU4) in leukocyte (white blood cell) adhesion. Our group has developed specific inhibitors for these enzymes with nanomolar potency. These compounds are important new tools for understanding the role of these enzymes in biochemical regulation of membrane receptors.

Current projects in the group are improving on the selectivity of NEU inhibitors and generating modified inhibitors to understand the specific recognition features of the enzyme active site.

Substrate specificity of membrane enzymes (Neuraminidases and Sphingomyelinase)

An important prerequisite for the design of probes and inhibitors is an established understanding of enzyme specificity and substrate tolerance. Our group uses chemical and chemoenzymatic synthesis to design probes of enzyme specificity. We have examined NEU and sphingomyelinase enzymes using this strategy. These data are in important asset for ongoing medicinal chemistry and chemical biology studies of these enzymes.

Current projects in the group are testing poly-sialoside substrates of NEU including disialo glycolipids and polysialic acids.

Bioconjugate strategies (Lipids, Cells, and Glycoconjugates)

Synthetic strategies for controlled modification of biomolecules in vitro or in cells is a rapidly evolving area of chemical biology. Our group is interested in the development and application of new labeling strategies that provide access to modified lipids, glycolipids, proteins, and glycoproteins. We have previously used metabolic labeling as well as chemical and chemoenzymatic synthesis for these systems.

Current projects in the group are applying chemoenzymatic and bioconjugate strategies to unusual glycoproteins.

Leukocyte receptor function (LFA-1 and CD45)

White blood cells (leukocytes) are critical part of the immune system. Leukocytes use adhesion receptors to control interactions between host cells and other immune cells. As a result, adhesion receptors regulate specific contacts (and their duration). Understanding the biochemical mechanisms of these interactions can help to develop new anti-inflammatory therapeutics. Our group is specifically interested in understanding the role of glycolipids and glycosylation in regulating these adhesion receptors.

Current projects in the group are studying the influence of glycolipid composition on LFA-1 and CD22 function on leukocytes.

Phosphatase enzyme inhibitors

Phosphatase enzymes are the biochemical antithesis of kinases – removing phosphate groups from proteins and other biomolecules. While kinases have become a common target for drug development, phosphatases have seen limited applications in medicinal chemistry. Our group previously developed a modular strategy for designing protein tyrosine phosphatase inhibitors using solid-phase peptide synthesis (SPPS). We have also applied similar chemical strategies to glycosyl phosphatase substrates important for diabetes.

Current projects in the group are testing the utility of alpha-bromobenzyl phosphonates in the structural biology of PTPase enzymes.

Selected Publications

  1. Albohy, A., Zhang, Y., Smutova, V., Pshezhetsky, A. V., and Cairo, C. W. (2013) Identification of Selective Nanomolar Inhibitors of the Human Neuraminidase, NEU4. ACS Med Chem Lett 4, 532-537
  2. Zou, C. X., Loka, R. S., Zhang, Y., and Cairo, C. W. (2013) Glycoform Remodeling Generates a Synthetic T Cell Phenotype. Bioconjugate Chem. 24, 907-914
  3. Cairo, C. W. (2014) Inhibitors of the human neuraminidase enzymes. MedChemComm 5, 1067-1074
  4. Downey, A. M., and Cairo, C. W. (2014) Synthesis of [small alpha]-brominated phosphonates and their application as phosphate bioisosteres. MedChemComm 5, 1619-1633
  5. Li, C., Key, J. A., Jia, F., Dandapat, A., Hur, S., and Cairo, C. W. (2014) Practical labeling methodology for choline-derived lipids and applications in live cell fluorescence imaging. Photochem. Photobiol. 90, 686-695
  6. Silvestri, I., Testa, F., Zappasodi, R., Cairo, C. W., Zhang, Y., Lupo, B., Galli, R., Di Nicola, M., Venerando, B. V., and Tringali, C. (2014) Sialidase NEU4 is involved in glioblastoma stem cell survival. Cell Death Differ. 5, e1381
  7. Smutova, V., Albohy, A., Pan, X., Korchagina, E., Miyagi, T., Bovin, N., Cairo, C. W., and Pshezhetsky, A. V. (2014) Structural Basis for Substrate Specificity of Mammalian Neuraminidases. PLoS One 9, e106320
  8. Hernandez Armada, D., Santos, J. T., Richards, M. R., and Cairo, C. W. (2015) Protecting group-free immobilization of glycans for affinity chromatography using glycosylsulfonohydrazide donors. Carbohydr. Res. 417, 109-116
  9. Slaney, A. M., Dijke, I. E., Jeyakanthan, M., Li, C., Zou, L., Plaza-Alexander, P., Meloncelli, P. J., Bau, J. A., Allan, L. L., Lowary, T. L., West, L. J., Cairo, C. W., and Buriak, J. M. (2016) Conjugation of A and B Blood Group Structures to Silica Microparticles for the Detection of Antigen-Specific B Cells. Bioconjug. Chem. 27, 705-715
  10. Yang, E. H., Rode, J., Howlader, M. A., Eckermann, M., Santos, J. T., Hernandez Armada, D., Zheng, R., Zou, C., and Cairo, C. W. (2017) Galectin-3 alters the lateral mobility and clustering of β1-integrin receptors. PLoS One 12, e0184378
  11. Daskhan, G. C., Tran, H.-T. T., Meloncelli, P. J., Lowary, T. L., West, L. J., and Cairo, C. W. (2018) Construction of Multivalent Homo- and Heterofunctional ABO Blood Group Glycoconjugates Using a Trifunctional Linker Strategy. Bioconjugate Chem. 29, 343-362
  12. Guo, T., Datwyler, P., Demina, E., Richards, M. R., Ge, P., Zou, C., Zheng, R., Fougerat, A., Pshezhetsky, A. V., Ernst, B., and Cairo, C. W. (2018) Selective Inhibitors of Human Neuraminidase 3. J. Med. Chem. 61, 1990-2008
  13. Guo, T., Heon-Roberts, R., Zou, C., Zheng, R., Pshezhetsky, A., and Cairo, C. W. (2018) Selective inhibitors of human neuraminidase 1 (NEU1). J. Med. Chem. 61, 11261-11279
  14. Hunter, C. D., Guo, T., Daskhan, G., Richards, M. R., and Cairo, C. W. (2018) Synthetic Strategies for Modified Glycosphingolipids and Their Design as Probes. Chem Rev 118, 8188-8241
  15. Hunter, C. D., Khanna, N., Richards, M. R., Rezaei Darestani, R., Zou, C., Klassen, J. S., and Cairo, C. W. (2018) Human Neuraminidase Isoenzymes Show Variable Activities for 9-O-Acetyl-sialoside Substrates. ACS Chem. Biol. 13, 922-932
  16. Richards, M. R., Guo, T., Hunter, C. D., and Cairo, C. W. (2018) Molecular dynamics simulations of viral neuraminidase inhibitors with the human neuraminidase enzymes: Insights into isoenzyme selectivity. Bioorg. Med. Chem. 26, 5349-5358