Compounds for inhibition of HIV infection by blocking HIV entry

Details Compounds for inhibition of HIV infection by blocking HIV entry Compounds for inhibition of HIV infection by blocking HIV entry

2007-07-10

2007-07-10

Powers, Fiona T. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S560000, C548S563000

Reexamination Certificate

active

10706027

ABSTRACT:
A group of compounds that inhibit HIV replication by blocking HIV entry was identified. Two representative compounds, designated NB-2 and NB-64, inhibited HIV replication (p24 production) with IC50values <0.5 μg/ml. It was proved that NB-2 and NB-64 are HIV entry inhibitors by targeting the HIV gp41 since: 1) they inhibited HIV-mediated cell fusion; 2) they inhibited HIV replication only when they were added to the cells less than one hour after virus addition; 3) they did not block the gp120-CD4 binding; 4) they did not interact with the coreceptor CXCR4 since they failed to block anti-CXCR4 antibody binding to CXCR4-expressing cells; 5) they blocked the formation of the gp41 core that is detected by sandwich enzyme linked immunosorbent assay (ELISA) using a conformation-specific MAb NC-1; 6) they inhibited the formation of the gp41 six-helix bundle revealed by fluorescence native-polyacrylamide gel electrophoresis (FN-PAGE); and 7) they blocked binding of D-peptide to the hydrophobic cavity within gp41 coiled coil domain, modeled by peptide IQN17. These results suggested that NB-2 and NB-64 may interact with the hydrophobic cavity and block the formation of the fusion-active gp41 coiled coil domain, resulting in inhibition of HIV-1 mediated membrane fusion and virus entry.

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