HIV receptor and co-receptor interactions

mteintzemontana.edu

CXCR4 is a G-protein coupled receptor for the chemokine CXCL12 (SDF-1), which is involved in cell migration and proliferation. It is also a co-receptor used by the X4 strains of HIV, which predominate at later stages of infection, and is required for their entry into target cells. We are designing and synthesizing non-peptide small molecule inhibitors of CXCR4 based on modeling studies. Lead compounds that compete with known CXCR4 antagonists, such as the peptide T-140, are being investigated for their ability to inhibit HIV infection in vitro, and to inhibit tumor cell metastasis in vitro and in a mouse model.

Selected Publications

Cheung, G.Y., Rigby, K., Wang, R., Queck, S.Y., Braughton, K.R., Whitney, A.R., Teintze, M., DeLeo, F.R., and Otto, M. :
Staphylococcus epidermidis strategies to avoid killing by human neutrophils.
PLoS Pathog. 6(10): pii: e1001133 (2010)

Wilkinson, R.A., Pincus, S.H., Shepard, J.B., Walton, S.K., Bergin, E.P., Labib, M. and Teintze, M. :
Novel compounds containing multiple guanide groups which bind the HIV co-receptor CXCR4.
Antimicrob. Agents Chemother. 55:255-263 (2011)

Wilkinson, R.A., Pincus,S.H., Song, K., Shepard, J.B., Weaver, A., Labib, M.E., and Teintze, M. :
Improved guanide compounds which bind the CXCR4 co-receptor and inhibit HIV infection.
Bioorg. Med. Chem. Lett. published online ahead of print: dx.doi.org/10.1016/j.bbr.2011.03.031(2013)

Keywords:
Biochemistry

Compounds with multiple biguanide groups such as chlorhexidine, alexidine, and PHMB are used as topical antimicrobials in a variety of settings. We have synthesized a series of small molecules with guanide, biguanide, and arylguanide functional groups that have comparable broad spectrum antibacterial activity, but lower cytotoxicity towards mammalian cells. We are investigating their mechanism of action and further optimizing their structures.

Keywords:
Biochemistry