Fig. 7: Mechanistic investigations of MMV687273 (SQ109).
a IC50 for MMV687273 (SQ109) on late-stage gametocytes (LG, stage IV/V), early-stage gametocytes (EG, stage II/III) or asexual parasites (ABS) tested on the same assay platform (PrestoBlue®) for 48 h drug pressure. Data are from three independent biological repeats (n = 3), performed in technical triplicates, mean ± S.E indicated. 95% confidence intervals on each point indicated as ribbons on each sigmoidal curve. IC50 ABS: 1.39 ± 0.090 µM; IC50 EG: 0.383 ± 0.108 µM; IC50 LG: 0.109 ± 0.002 µM; **p = 0.0052 ABS vs LG; *p = 0.036 ABS vs EG, paired, two-tailed t test. b IC50 for MMV687273 (SQ109) tested on stage IV/V gametocytes after 12, 24 or 48 h drug pressure (PrestoBlue® assay). Data are from three independent experiments (n = 3), each in triplicate, ±S.E. c The percentage of inhibition of stage IV/V viability under 1 µM pressure of MMV687273 (SQ109) compared to MMV180402 (2-adamantanamine) or the parent compound ethambutol (MMV687801, S,S-ethambutol and ethambutol.HCl). Data are from three independent biological repeats (n = 3), in technical duplicates each, mean ± S.E indicated. ***p = 0.0006, **p = 0.0052, paired, two-tailed t test. d Structure of the P. falciparum V-type H+-ATPase subunit A (PfvapA, PF3D7_1311900, cyan in all cases, code Q76NM6 Swiss Model Repository), using the mammalian V-type ATPase from rat brain (6vq6.1) as template. The soluble V1 and membrane-associated Vo domains of the mammalian complex is indicated. e Top view of the V1 domain, indicating the overlap of PfvapA (cyan) with subunit A of the mammalian complex (purple) compared to subunit B (turquoise) and f structure of PfvapA alone with side view. Bound ADP is indicated in red, the mutations in PfvapA is as follows: Q225K in orange, R353K in yellow.
