Inhibition of cell surface protein disulfide isomerase

Details Inhibition of cell surface protein disulfide isomerase Inhibition of cell surface protein disulfide isomerase

2005-09-27

2005-09-27

Weber, Jon (Department: 1653)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heavy metal containing

C562S030000, C424S620000, C548S240000

Reexamination Certificate

active

06949665

ABSTRACT:
The invention provides anti-thiol reagents which inhibit enzyme activity of cell-associated protein disulfide isomerase (PDI) by oxidizing or blocking PDI active site vicinal thiol groups which normally participate in disulfide bond rearrangement of PDI substrates. Inhibition of this PDI function is particularly useful in blocking PDI-mediated entry of HIV or other virions into a host cell, as well as inhibiting lymphocyte traffic through the lymph nodes. The invention further provides an assay for the identification of such PDI inhibitors based on the discovery that inhibitors of the invention also induce shedding of the leucocyte L-selectin adhesion molecule.

REFERENCES:
Barbouche et al., “Protein-disulfide Isomerase-mediated Reduction of Two Disulfide Bonds of HIV Envelope Glycoprotein 120 Occurs Post-CXCR4 Binding and Is Required for Fusion”, J. Biol. Chem. 2003; 278:3131-3136.
Fenouillet et al., “Catalytic Activity of Protein Disulfide Isomerase Is Involved in Human Immunodeficiency Virus Envelope-Mediated Membrane Fusion after CD4 Cell Binding”, Journal of Infectious Diseases 2001; 183:744-52.
Gallina et al., “Inhibitors of Protein-Disulfide Isomerase Prevent Cleavage of Disulfide Bonds in Receptor-bound Glycoprotein 120 and Prevent HIV-1 Entry”, J. Biol. Chem. 2002; 277:50579-50588.
Goldsmith et al., “HIV entry: are all receptors created equal?”, Nature Immunology 2002; 3:709-710.
Matthias et al., “Disulfide exchange in domain 2 of CD4 is required for entry of HIV-1”, Nature Immunology 2002; 3:727-732. Corrected (details online); doi:10.1038
i815 (http://immunol.nature.com).

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