TY - JOUR
T1 - Inhibition of Calcium Dependent Protein Kinase 1 (CDPK1) by Pyrazolopyrimidine Analogs Decreases Establishment and Reoccurrence of Central Nervous System Disease by Toxoplasma gondii
AU - Rutaganira, Florentine U.
AU - Barks, Jennifer
AU - Dhason, Mary Savari
AU - Wang, Qiuling
AU - Lopez, Michael S.
AU - Long, Shaojun
AU - Radke, Joshua B.
AU - Jones, Nathaniel G.
AU - Maddirala, Amarendar R.
AU - Janetka, James W.
AU - El Bakkouri, Majida
AU - Hui, Raymond
AU - Shokat, Kevan M.
AU - Sibley, L. David
N1 - Funding Information:
We are grateful to Keliang Tang who performed the initial studies on enzyme kinetics and established the enzyme assays and to Martin John Rodgers for his early support of this project. We also thank John R. Walker of the Structural Genomics Consortium for verifying the crystallographic structures and for their deposition into the Protein Data Bank and the UCSF NMR Lab and QB3/ Chemistry Mass Spectrometry Facility (University of California, Berkeley) for access to instrumentation for compound characterization. Supported by a grant from the NIH (AI094098 to K.M.S. and L.D.S.). The compounds reported here are the subject of patent applications filed by UCSF and Washington University.
Funding Information:
We are grateful to Keliang Tang who performed the initial studies on enzyme kinetics and established the enzyme assays and to Martin John Rodgers for his early support of this project. We also thank John R. Walker of the Structural Genomics Consortium for verifying the crystallographic structures and for their deposition into the Protein Data Bank and the UCSF NMR Lab and QB3/Chemistry Mass Spectrometry Facility (University of California, Berkeley) for access to instrumentation for compound characterization. Supported by a grant from the NIH (AI094098 to K.M.S. and L.D.S.). The compounds reported here are the subject of patent applications filed by UCSF and Washington University.
Publisher Copyright:
© 2017 American Chemical Society.
PY - 2017/12/28
Y1 - 2017/12/28
N2 - Calcium dependent protein kinase 1 (CDPK1) is an essential enzyme in the opportunistic pathogen Toxoplasma gondii. CDPK1 controls multiple processes that are critical to the intracellular replicative cycle of T. gondii including secretion of adhesins, motility, invasion, and egress. Remarkably, CDPK1 contains a small glycine gatekeeper residue in the ATP binding pocket making it sensitive to ATP-competitive inhibitors with bulky substituents that complement this expanded binding pocket. Here we explored structure-activity relationships of a series of pyrazolopyrimidine inhibitors of CDPK1 with the goal of increasing selectivity over host enzymes, improving antiparasite potency, and improving metabolic stability. The resulting lead compound 24 exhibited excellent enzyme inhibition and selectivity for CDPK1 and potently inhibited parasite growth in vitro. Compound 24 was also effective at treating acute toxoplasmosis in the mouse, reducing dissemination to the central nervous system, and decreasing reactivation of chronic infection in severely immunocompromised mice. These findings provide proof of concept for the development of small molecule inhibitors of CDPK1 for treatment of CNS toxoplasmosis.
AB - Calcium dependent protein kinase 1 (CDPK1) is an essential enzyme in the opportunistic pathogen Toxoplasma gondii. CDPK1 controls multiple processes that are critical to the intracellular replicative cycle of T. gondii including secretion of adhesins, motility, invasion, and egress. Remarkably, CDPK1 contains a small glycine gatekeeper residue in the ATP binding pocket making it sensitive to ATP-competitive inhibitors with bulky substituents that complement this expanded binding pocket. Here we explored structure-activity relationships of a series of pyrazolopyrimidine inhibitors of CDPK1 with the goal of increasing selectivity over host enzymes, improving antiparasite potency, and improving metabolic stability. The resulting lead compound 24 exhibited excellent enzyme inhibition and selectivity for CDPK1 and potently inhibited parasite growth in vitro. Compound 24 was also effective at treating acute toxoplasmosis in the mouse, reducing dissemination to the central nervous system, and decreasing reactivation of chronic infection in severely immunocompromised mice. These findings provide proof of concept for the development of small molecule inhibitors of CDPK1 for treatment of CNS toxoplasmosis.
UR - http://www.scopus.com/inward/record.url?scp=85040008072&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.7b01192
DO - 10.1021/acs.jmedchem.7b01192
M3 - Article
C2 - 28933846
AN - SCOPUS:85040008072
SN - 0022-2623
VL - 60
SP - 9976
EP - 9989
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 24
ER -