Abstract

This research will develop compounds that interfere with attachment of influenza virus to cells (and detachment from cells). Its objectives are: . To develop synthetic routes to analogs of sialic acids and structurally related compounds, and to use these compounds to block the sialic acid binding sites of viral hemagglutinin (HA) and of neuraminidase (NA). . To prepare bi, tri-, and multivalent versions of these compounds, to take advantage of cooperative polyvalent interaction between them and HA and NA on the surface of the virus. . To prepare polymeric, polyvalent compounds by free-radical polymerization of appropriately functionalized monomers containing analogs of sialic acids, and to evaluate the importance of """"""""steric inhibition"""""""" of binding of virus to cell using these polymers. . To develop and implement new types of assays relevant to these interactions, including assays based on embryonated chicken eggs and on affinity capillary electrophoresis. . To begin to extend the general principles established in studying influenza virus to other viruses and to bacterial pathogens.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM039589-10S1
Application #
6240453
Study Section
Project Start
1996-09-01
Project End
1998-07-31
Budget Start
1996-10-01
Budget End
1997-09-30
Support Year
10
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
Harvard University
Department
Type
DUNS #
071723621
City
Cambridge
State
MA
Country
United States
Zip Code
02138

  Publications

Verdine, Gregory L; Norman, Derek P G (2003) Covalent trapping of protein-DNA complexes. Annu Rev Biochem 72:337-66
Abdulaev, Najmoutin G; Strassmaier, Timothy T; Ngo, Tony et al. (2002) Grafting segments from the extracellular surface of CCR5 onto a bacteriorhodopsin transmembrane scaffold confers HIV-1 coreceptor activity. Structure 10:515-25
Lin, C H; Hare, B J; Wagner, G et al. (2001) A small domain of CBP/p300 binds diverse proteins: solution structure and functional studies. Mol Cell 8:581-90
Mantis, N J; Kozlowski, P A; Mielcarz, D W et al. (2001) Immunization of mice with recombinant gp41 in a systemic prime/mucosal boost protocol induces HIV-1-specific serum IgG and secretory IgA antibodies. Vaccine 19:3990-4001
Zhou, G; Ferrer, M; Chopra, R et al. (2000) The structure of an HIV-1 specific cell entry inhibitor in complex with the HIV-1 gp41 trimeric core. Bioorg Med Chem 8:2219-27
Huang, H; Harrison, S C; Verdine, G L (2000) Trapping of a catalytic HIV reverse transcriptase*template:primer complex through a disulfide bond. Chem Biol 7:355-64
Ferrer, M; Harrison, S C (1999) Peptide ligands to human immunodeficiency virus type 1 gp120 identified from phage display libraries. J Virol 73:5795-802
Frankel, A D; Young, J A (1998) HIV-1: fifteen proteins and an RNA. Annu Rev Biochem 67:1-25
Huang, H; Chopra, R; Verdine, G L et al. (1998) Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase: implications for drug resistance. Science 282:1669-75
Weissenhorn, W; Calder, L J; Dessen, A et al. (1997) Assembly of a rod-shaped chimera of a trimeric GCN4 zipper and the HIV-1 gp41 ectodomain expressed in Escherichia coli. Proc Natl Acad Sci U S A 94:6065-9

Showing the most recent 10 out of 39 publications