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

Jandeli Niemand, Riëtte Van Biljon, Mariëtte Van Der Watt, Ashleigh Van Heerden, Janette Reader, Roelof Van Wyk, Lindsey Orchard, Kelly Chibale, Manuel Llinás, Lyn Marié Birkholtz

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2904-2916
Number of pages13
JournalACS Infectious Diseases
Volume7
Issue number10
DOIs
StatePublished - Oct 8 2021

All Science Journal Classification (ASJC) codes

  • Infectious Diseases

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