Suppression of Drug Resistance in Dengue Virus

Mateo, Roberto; Nagamine, Claude M.; Kirkegaard, Karla

Biochemical dominance of ST-148-susceptible core proteins. The most likely mechanism for the ability of drugsusceptible core protein to inhibit the function of drug-resistant core protein is the formation of chimeric oligomers. To test whether the drug-susceptible and drug-resistant proteins could coassemble, their cellular localizations ( Fig. 2A) in single infections and coinfections were monitored. Scatturo et al. (13) found previously that wild-type core protein was predominately associated with cytoplasmic membranes in the absence of ST-148 ( Fig. 2B , top row). In the presence of ST-148, the wild-type core protein was also found in nuclear fractions, which might contribute to the compound's antiviral activity (13) . In contrast, the Figure 2D shows the expected amounts of core membrane association if the patterns are additive (Fig. 2D , left). The observed pattern (Fig. 2D , right) instead mimicked that of drug-susceptible virus alone (Fig. 2C, left) . Therefore, the wild-type, drug-susceptible phenotype is dominant over the drug-resistant phenotype in the presence of ST-148. That the drug-resistant protein fractionates differently when in the presence of the drug-susceptible protein supports the hypothesis that the two kinds of proteins coassemble.