Extended Data Figure 6. In vivo transmission-stage efficacy study of BRD7929.

a, Oral doses of BRD7929 2 days before feeding mosquitoes upon infected mice resulted in complete blocking of transmission at 5 mg kg⁻¹, and reduced transmission activity at 1.25 mg kg⁻¹ and 0.31 mg kg⁻¹ (n = 2 for each group, this study was conducted once). b, Mosquitoes fed on vehicle-treated mice showed heavy infection 1 week after feeding, while mosquitoes fed on treated mice showed no or very few oocysts in the midguts. Representative images are shown; scale bars, 100 µm. c, To confirm that BRD7929 eliminates mature gametocytes in the host circulation rather than killing gametes, zygotes or ookinetes in the mosquito midgut, CD-1 mice infected with P. berghei (parasitaemia between 11 to 19%) were first treated with BRD7929 (oral, 25 mg kg⁻¹). Infected mice were then exposed to female A. stephensi mosquitoes for blood feeding 1, 4 or 10 days after the treatment. Blood samples were also obtained before the blood feedings to measure the plasma concentration of remaining BRD7929 (n = 2 for each group, this study was conducted once). No oocysts were found in midguts dissected from mosquitoes from all time points, whereas 896.5, 170.5 and 8.6 ng ml⁻¹ of the compound remained in the circulation 1, 4 and 10 days after respectively treatment, respectively, suggesting that BRD7929 eliminated mature gametocytes in the mice. d–f. In vivo transmission-stage efficacy study of BRD7929 (humanized mouse model). huRBC NSG mice were infected with the blood-stage P. falciparum 3D7^HLH/BRD for 2 weeks to allow the gametocytes to mature fully and were treated with a single oral dose of BRD7929 (12.5 mg kg⁻¹). n = 2 for each group, this study was conducted once. Blood samples collected from vehicle- and BRD7929-treated mice were tested for the presence of gametocyte-specific transcripts using mature gametocyte marker (PF3D7_1438800; d) and immature gametocyte marker (PF3D7_1477700; e). PF3D7_1120200 (P. falciparum UCE), a constitutively expressed gene, was used as a positive control marker for parasite detection (f). Data are mean ± s.d.; three technical replicates for each biological sample.