During @entity2858 reverse transcription, there are increasing opportunities for nucleos(t)ide (NRTI) or non- @entity2353 (NNRTI) reverse transcriptase inhibitors to stop elongation of the nascent viral DNA. In addition, @entity138 inhibitors appear to influence the kinetics of vDNA synthesis differently. While cell-free kinetic inhibition constants have provided detailed mechanistic insight, these assays are dependent on experimental conditions that may not mimic the cellular milieu. Here we describe a novel cell-based strategy to provide a measure of the intrinsic inhibition efficiencies of clinically relevant @entity138 inhibitors on a per-stop-site basis. To better compare inhibition efficiencies among @entity2858 @entity138 inhibitors that can stop reverse transcription at any number of different stop sites, their basic probability, p, of getting stopped at any potential stop site was determined. A relationship between qPCR-derived EC50 values and this basic probability, p, enabled determination of p by successive approximation. On a per-stop-site basis, @entity15833 (TFV) exhibited 1.4-fold greater inhibition efficiency than @entity15832 (FTC), and as a class, both NRTIs exhibited an 8- to 11-fold greater efficiency than efavirenz (EFV). However, as more potential stops-sites were considered, the probability of reverse transcription failing to reach the end of the template approached equivalence between both classes of @entity138 inhibitors. Overall, this novel strategy provides a quantitative measure of the intrinsic inhibition efficiencies of @entity138 inhibitors in the natural cellular milieu and thus may further understanding of drug efficacy. This approach also has applicability for understanding the impact of viral polymerase-based inhibitors (alone or in combination) in other virus systems.

A Cell-Based Strategy to Assess Intrinsic Inhibition Efficiencies of XXXX Reverse Transcriptase Inhibitors.

@entity2353 :: ('CHEBI:33838', 'Chemical') :: ['nucleoside'] @entity138 :: ('MESH:C563738', 'Disease') :: ['RT'] @entity2858 :: ('11676', 'Species') :: ['HIV-1'] @entity15832 :: ('MESH:C122114', 'Chemical') :: ['emtricitabine'] @entity15833 :: ('MESH:C096918', 'Chemical') :: ['tenofovir']
@entity2858 :: (11676,Species) :: ['HIV-1']
