Development of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) inhibitors with potent anti-toxoplasma activity.
Toxoplasmosis is a disease of prominent health concern that is caused by the protozoan parasite Toxoplasma gondii. Proliferation of T. gondii is dependent on its ability to invade host cells, which is mediated in part by calcium-dependent protein kinase 1 (CDPK1). We have developed ATP competitive inhibitors of TgCDPK1 that block invasion of parasites into host cells, preventing their proliferation. The presence of a unique glycine gatekeeper residue in TgCDPK1 permits selective inhibition of the parasite enzyme over human kinases. These potent TgCDPK1 inhibitors do not inhibit the growth of human cell lines and represent promising candidates as toxoplasmosis therapeutics.
Department of Chemistry, University of Washington, Seattle, Washington, USA.
Steven M
SM
Johnson
Ryan C
RC
Murphy
Jennifer A
JA
Geiger
Amy E
AE
DeRocher
Zhongsheng
Z
Zhang
Kayode K
KK
Ojo
Eric T
ET
Larson
B Gayani K
BG
Perera
Edward J
EJ
Dale
Panqing
P
He
Molly C
MC
Reid
Anna M W
AM
Fox
Natascha R
NR
Mueller
Ethan A
EA
Merritt
Erkang
E
Fan
Marilyn
M
Parsons
Wesley C
WC
Van Voorhis
Dustin J
DJ
Maly
D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003049:Coccidiostats / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004351:Drug Resistance; D057075:Enzyme Assays; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014122:Toxoplasma / Q000187:drug effects* / Q000201:enzymology; D017871:Calcium-Calmodulin-Dependent Protein Kinases
D003049:Coccidiostats; D009281:Naphthalenes; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D015800:Protozoan Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D017871:Calcium-Calmodulin-Dependent Protein Kinases