Journal
ACS INFECTIOUS DISEASES
Volume 7, Issue 10, Pages 2904-2916Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.1c00373
Keywords
gametocyte; drug response; kinase; stage-specific; chemogenomic; Plasmodium
Categories
Funding
- South African Medical Research Council
- Department of Science and Innovation South African Research Chairs Initiative [84627]
- NIH [R01 AI125565]
- International Society of Infectious diseases Small Grants program
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The study reveals differential activity of kinase inhibitors against different stages of Plasmodium falciparum gametocytes through transcriptome fingerprinting, highlighting the importance of targeting late-stage gametocytes for the development of transmission-blocking antimalarials.
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.
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