TY - JOUR
T1 - Chemogenomic Fingerprints Associated with Stage-Specific Gametocytocidal Compound Action against Human Malaria Parasites
AU - Niemand, Jandeli
AU - Van Biljon, Riëtte
AU - Van Der Watt, Mariëtte
AU - Van Heerden, Ashleigh
AU - Reader, Janette
AU - Van Wyk, Roelof
AU - Orchard, Lindsey
AU - Chibale, Kelly
AU - Llinás, Manuel
AU - Birkholtz, Lyn Marié
N1 - Publisher Copyright:
© 2021 The Authors. Published by American Chemical Society.
PY - 2021/10/8
Y1 - 2021/10/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85117507736&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85117507736&partnerID=8YFLogxK
U2 - 10.1021/acsinfecdis.1c00373
DO - 10.1021/acsinfecdis.1c00373
M3 - Article
C2 - 34569223
AN - SCOPUS:85117507736
SN - 2373-8227
VL - 7
SP - 2904
EP - 2916
JO - ACS Infectious Diseases
JF - ACS Infectious Diseases
IS - 10
ER -