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5th International Workshop on HIV Drug Resistance & Treatment Strategies4-8 June 2001, Scottsdale, Arizona |
The compound SJ-3366 inhibits HIV-1 and HIV-2 through specific inhibition of the reverse transcriptase (RT) of HIV-1 and inhibition of envelope mediated infection events (HIV-1 and HIV-2). Against HIV-1, the non-nucleoside reverse transcriptase inhibitor (NNRTI) exhibits low nanomolar to sub-nanomolar IC95 concentrations. Inhibition of virus entry occurs at 100-fold higher concentrations. SJ-3366 inhibits the initial events of infection by interfering with a postattachment event involved in virus entry. SJ-3366 does not interfere with the interaction of CD4 and gp120 or virus attachment to the surface of the target cell, but does interfere with the ability of the virus to penetrate the cell membrane. We have shown in virus/cell complex assays that SJ-3366 may act similarly to the peptide T20 by binding to a tertiary complex formed upon interaction of the virus and the cell. This cell surface mechanism is the primary inhibitory activity of SJ-3366 against HIV-2 and the secondary (in terms of potency) mechanism of action against HIV-1. SJ-3366 also acts as a typical NNRTI against HIV-1. The compound inhibits RT at low nanomolar concentrations in biochemical assays, exhibiting Ki values of 1–3 nM, but is totally inactive against HIV-2 RT in the same assays. With both HIV-1 and HIV-2, the selection of resistant strains in cell culture was rapid. With HIV- 1, we have shown that the initial passages of virus yielded resistant strains that were no longer susceptible to the attachment inhibition mechanism, resulting in a strain of virus with approximately 1000-fold loss in sensitivity to SJ-3366. A variety of amino acid changes were detected in the envelope of this virus. With increasing passage, a variety of NNRTI resistance-engendering amino acid changes appeared. At later passages, increasing resistance was achieved without the accumulation of additional mutations in RT. New amino changes did appear, however, in the envelope. With HIV-2, resistance also appears rapidly and amino acid changes are detected only in env. Structure activity assays have been performed to attempt to assign these two antiviral activities to distinct features of the molecule and these data suggest a complex interaction of molecular features results in virus inhibition.
PRESENTING AUTHOR: RW Buckheit Jr
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