Fig. 6: CQ-resistance-conferring isoforms of PfCRT increase parasite susceptibility to saquinavir.

a The antiplasmodial activities of CQ and saquinavir (SQV) against CQ-sensitive (C2^GC03 and 3D7) and CQ-resistant (C6^7G8, C4^Dd2, 7G8 and Dd2) parasites in the presence or absence of verapamil (VP). The data are the mean of n = 5 independent experiments (each yielding similar results) and the error is the SEM. The asterisks denote a significant difference from the relevant control (red asterisks, C4^Dd2 or Dd2 control; orange asterisks, C6^7G8 or 7G8 control; blue asterisks, C2^GC03 or 3D7 control); **P < 0.01, ***P < 0.001, ns: non-significant (one-way ANOVA). The source datasets are provided as a Source Data file. b Mechanistic model for the increased susceptibility of CQ-resistant parasites to SQV. PfCRT^3D7 (wild-type PfCRT) lacks detectable CQ transport activity, whereas the CQ-resistance-conferring isoforms of PfCRT (mutant PfCRT) efflux CQ from the DV. VP inhibits CQ transport via the mutant transporters, thereby re-sensitising the CQ-resistant parasites to this antimalarial drug. By contrast, PfCRT^3D7 has a greater capacity for transporting SQV out of the DV than do the mutant isoforms. Moreover, it is the wild-type protein that confers reduced sensitivity to SQV. Given that VP (1) inhibits SQV transport via both the wild-type and mutant PfCRT transporters and (2) increases the antiplasmodial activity of SQV in all of the parasite types, our findings indicate that SQV acts on a target within the DV.