DAPY non-nucleoside inhibitors of HIV-1 reverse transcriptase possess high activity in microbicide assays and have potential for prevention of sexual transmission of HIV
Abstract number: 10.1111/j.1198-743X.2004.902_o130.x
Several diaryl-pyrimidine (DAPY) compounds have nanomolar activity in cell-based assays on wild type and mutant HIV-1. They bind into the non-nucleoside site of HIV-1 reverse transcriptase (NNRT). Three DAPY compounds are presently in clinical studies.
In parallel, microbicide assays have been carried out on DAPYs in order to assess their potential for prevention of transmission of HIV.
In a first set of experiments, monocyte-derived dendritic and autologous CD4+ T cells (MO-DC/T) were infected with HIV-1 Ba-L, washed and treated for 14 days with the test compound, yielding the 50% effective concentration (EC50).
In a second set, exposure to compound was 24 h. After 24 h, cells were washed and co-cultured for 14 days without compound, followed by secondary culture with PHA/IL-2 blasts.
In a third set, virus was immobilized on poly-l-lysine and pretreated with compound for 1 h in the absence of cells. After washing, MO-DC/T were added and cultured during 14 days.
EC50s of the DAPYs in the 14-days experiment ranged between 0.4 and 3 nm. For comparison, EC50s for UC-781 and PMPA in this test were 53 and 106 nm, respectively. Dapivirine (TMC120-R147681), the prototype DAPY, showed only a small increase in EC50 in the 24-h assay and completely protected against HIV between 10 and 100 nm, whereas 100-fold higher concentrations were required with UC-781 and PMPA. In the 1-h assay, dapivirine completely inhibited replication between 10 and 100 nm, while UC-781 required 100-fold higher concentrations.
NNRTIs of the DAPY-class of compounds are highly potent inhibitors of HIV-1 replication in microbicide assays which mimick conditions of sexual transmission of HIV. DAPYs, such as dapivirine, may possess virucidal activity against HIV in the absence of target cells.
DAPY NNRTIs present high potential for development as microbicides in order to prevent sexual transmission of HIV, using vehicles such as gels and intravaginal rings."
|Session name:||XXIst ISTH Congress|
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