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

  • ACS Infect Dis. 2021 Oct 8;7(10):2904-2916. doi: 10.1021/acsinfecdis.1c00373.
Jandeli Niemand  1  2 ,  Riëtte van Biljon  1 ,  Mariëtte van der Watt  1 ,  Ashleigh van Heerden  1 ,  Janette Reader  1 ,  Roelof van Wyk  1 ,  Lindsey Orchard  3 ,  Kelly Chibale  4  5 ,  Manuel Llinás  3  6 ,  Lyn-Marié Birkholtz  1  2
Affiliations
  • 1. Department of Biochemistry, Genetics and Microbiology, University of Pretoria, Hatfield, Pretoria 0028, South Africa.
  • 2. Institute for Sustainable Malaria Control, University of Pretoria, Hatfield, Pretoria 0028, South Africa.
  • 3. Department of Biochemistry & Molecular Biology and the Huck Centre for Malaria Research, Pennsylvania State University, University Park, Pennsylvania 16802, United States.
  • 4. Drug Discovery and Development Centre (H3D), University of Cape Town, Rondebosch, Cape Town, 7701, South Africa.
  • 5. South African Medical Research Council, Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa.
  • 6. Department of Chemistry, Pennsylvania State University, University Park, Pennsylvania 16802, United States.
PMID: 34569223 DOI: 10.1021/acsinfecdis.1c00373
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.

Keywords
Plasmodium; chemogenomic; drug response; gametocyte; kinase; stage-specific.
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