Chemogenomic Fingerprints Associated with Stage-Specific Gametocytocidal Compound Action against Human Malaria Parasites

Kinase-focused inhibitors
previously revealed compounds with differential
activity against different stages of Plasmodium falciparum gametocytes. MMV666810, a 2-aminopyrazine, is more active on late-stage
gametocytes, while a pyrazolopyridine, MMV674850, preferentially targets
early-stage gametocytes. Here, we probe the biological mechanisms
underpinning this differential stage-specific killing using in-depth
transcriptome fingerprinting. Compound-specific chemogenomic profiles
were observed with MMV674850 treatment associated with biological
processes shared between asexual blood stage parasites and early-stage
gametocytes but not late-stage gametocytes. MMV666810 has a distinct
profile with clustered gene sets associated primarily with late-stage
gametocyte development, including Ca2+-dependent protein
kinases (CDPK1 and 5) and serine/threonine protein kinases (FIKK).
Chemogenomic profiling therefore highlights essential processes in
late-stage gametocytes, on a transcriptional level. This information
is important to prioritize compounds that preferentially compromise
late-stage gametocytes for further development as transmission-blocking
antimalarials.