Select pyrimidinones inhibit the propagation of the malarial parasite, Plasmodium falciparum

Annette N. Chiang; Juan Carlos Valderramos; Raghavan Balachandran; Raj J. Chovatiya; Brian P. Mead; Corinne Schneider; Samantha L. Bell; Michael G. Klein; Donna M. Huryn; Xiaojiang S. Chen; Billy W. Day; David A. Fidock; Peter Wipf; Jeffrey L. Brodsky

doi:10.1016/j.bmc.2009.01.024

Select pyrimidinones inhibit the propagation of the malarial parasite, Plasmodium falciparum

Annette N. Chiang, Juan Carlos Valderramos, Raghavan Balachandran, Raj J. Chovatiya, Brian P. Mead, Corinne Schneider, Samantha L. Bell, Michael G. Klein, Donna M. Huryn, Xiaojiang S. Chen, Billy W. Day, David A. Fidock, Peter Wipf, Jeffrey L. Brodsky^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

125 Scopus citations

Abstract

Plasmodium falciparum, the Apicomplexan parasite that is responsible for the most lethal forms of human malaria, is exposed to radically different environments and stress factors during its complex lifecycle. In any organism, Hsp70 chaperones are typically associated with tolerance to stress. We therefore reasoned that inhibition of P. falciparum Hsp70 chaperones would adversely affect parasite homeostasis. To test this hypothesis, we measured whether pyrimidinone-amides, a new class of Hsp70 modulators, could inhibit the replication of the pathogenic P. falciparum stages in human red blood cells. Nine compounds with IC₅₀ values from 30 nM to 1.6 μM were identified. Each compound also altered the ATPase activity of purified P. falciparum Hsp70 in single-turnover assays, although higher concentrations of agents were required than was necessary to inhibit P. falciparum replication. Varying effects of these compounds on Hsp70s from other organisms were also observed. Together, our data indicate that pyrimidinone-amides constitute a novel class of anti-malarial agents.

Original language	English (US)
Pages (from-to)	1527-1533
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry
Volume	17
Issue number	4
DOIs	https://doi.org/10.1016/j.bmc.2009.01.024
State	Published - Feb 15 2009
Externally published	Yes

Keywords

ATPase
Hsp40
Hsp70
J domain
Molecular chaperone
Pyrimidinone

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmc.2009.01.024

Cite this

Chiang, A. N., Valderramos, J. C., Balachandran, R., Chovatiya, R. J., Mead, B. P., Schneider, C., Bell, S. L., Klein, M. G., Huryn, D. M., Chen, X. S., Day, B. W., Fidock, D. A., Wipf, P., & Brodsky, J. L. (2009). Select pyrimidinones inhibit the propagation of the malarial parasite, Plasmodium falciparum. Bioorganic and Medicinal Chemistry, 17(4), 1527-1533. https://doi.org/10.1016/j.bmc.2009.01.024

@article{440556edbb4c46208bd9f5d90d3cda35,

title = "Select pyrimidinones inhibit the propagation of the malarial parasite, Plasmodium falciparum",

abstract = "Plasmodium falciparum, the Apicomplexan parasite that is responsible for the most lethal forms of human malaria, is exposed to radically different environments and stress factors during its complex lifecycle. In any organism, Hsp70 chaperones are typically associated with tolerance to stress. We therefore reasoned that inhibition of P. falciparum Hsp70 chaperones would adversely affect parasite homeostasis. To test this hypothesis, we measured whether pyrimidinone-amides, a new class of Hsp70 modulators, could inhibit the replication of the pathogenic P. falciparum stages in human red blood cells. Nine compounds with IC50 values from 30 nM to 1.6 μM were identified. Each compound also altered the ATPase activity of purified P. falciparum Hsp70 in single-turnover assays, although higher concentrations of agents were required than was necessary to inhibit P. falciparum replication. Varying effects of these compounds on Hsp70s from other organisms were also observed. Together, our data indicate that pyrimidinone-amides constitute a novel class of anti-malarial agents.",

keywords = "ATPase, Hsp40, Hsp70, J domain, Molecular chaperone, Pyrimidinone",

author = "Chiang, {Annette N.} and Valderramos, {Juan Carlos} and Raghavan Balachandran and Chovatiya, {Raj J.} and Mead, {Brian P.} and Corinne Schneider and Bell, {Samantha L.} and Klein, {Michael G.} and Huryn, {Donna M.} and Chen, {Xiaojiang S.} and Day, {Billy W.} and Fidock, {David A.} and Peter Wipf and Brodsky, {Jeffrey L.}",

note = "Funding Information: This work was supported in part by a pilot grant from the University of Pittsburgh Drug Discovery Institute to J.L.B. R.J.C. was supported by a fellowship from the Beckman Foundation, and S.B. received funding from a Howard Hughes Medical Institute undergraduate research program. P.W. and D.M.H. thank the NIH-NIGMS for Grant P50-GM067082 for support of the CMLD program at the University of Pittsburgh. We also wish to thank Greg Blatch, James Burden, Pete Chambers, Doug Cyr, Myriam Gorospe, Michael Lyon, Richard Morimoto, Stephanie Nicolay, Bill Strieff, David Turner, and Stefan Werner for technical assistance and/or for providing reagents. ",

year = "2009",

month = feb,

day = "15",

doi = "10.1016/j.bmc.2009.01.024",

language = "English (US)",

volume = "17",

pages = "1527--1533",

journal = "Bioorganic and Medicinal Chemistry",

issn = "0968-0896",

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Chiang, AN, Valderramos, JC, Balachandran, R, Chovatiya, RJ, Mead, BP, Schneider, C, Bell, SL, Klein, MG, Huryn, DM, Chen, XS, Day, BW, Fidock, DA, Wipf, P & Brodsky, JL 2009, 'Select pyrimidinones inhibit the propagation of the malarial parasite, Plasmodium falciparum', Bioorganic and Medicinal Chemistry, vol. 17, no. 4, pp. 1527-1533. https://doi.org/10.1016/j.bmc.2009.01.024

TY - JOUR

T1 - Select pyrimidinones inhibit the propagation of the malarial parasite, Plasmodium falciparum

AU - Chiang, Annette N.

AU - Valderramos, Juan Carlos

AU - Balachandran, Raghavan

AU - Chovatiya, Raj J.

AU - Mead, Brian P.

AU - Schneider, Corinne

AU - Bell, Samantha L.

AU - Klein, Michael G.

AU - Huryn, Donna M.

AU - Chen, Xiaojiang S.

AU - Day, Billy W.

AU - Fidock, David A.

AU - Wipf, Peter

AU - Brodsky, Jeffrey L.

N1 - Funding Information: This work was supported in part by a pilot grant from the University of Pittsburgh Drug Discovery Institute to J.L.B. R.J.C. was supported by a fellowship from the Beckman Foundation, and S.B. received funding from a Howard Hughes Medical Institute undergraduate research program. P.W. and D.M.H. thank the NIH-NIGMS for Grant P50-GM067082 for support of the CMLD program at the University of Pittsburgh. We also wish to thank Greg Blatch, James Burden, Pete Chambers, Doug Cyr, Myriam Gorospe, Michael Lyon, Richard Morimoto, Stephanie Nicolay, Bill Strieff, David Turner, and Stefan Werner for technical assistance and/or for providing reagents.

PY - 2009/2/15

Y1 - 2009/2/15

N2 - Plasmodium falciparum, the Apicomplexan parasite that is responsible for the most lethal forms of human malaria, is exposed to radically different environments and stress factors during its complex lifecycle. In any organism, Hsp70 chaperones are typically associated with tolerance to stress. We therefore reasoned that inhibition of P. falciparum Hsp70 chaperones would adversely affect parasite homeostasis. To test this hypothesis, we measured whether pyrimidinone-amides, a new class of Hsp70 modulators, could inhibit the replication of the pathogenic P. falciparum stages in human red blood cells. Nine compounds with IC50 values from 30 nM to 1.6 μM were identified. Each compound also altered the ATPase activity of purified P. falciparum Hsp70 in single-turnover assays, although higher concentrations of agents were required than was necessary to inhibit P. falciparum replication. Varying effects of these compounds on Hsp70s from other organisms were also observed. Together, our data indicate that pyrimidinone-amides constitute a novel class of anti-malarial agents.

AB - Plasmodium falciparum, the Apicomplexan parasite that is responsible for the most lethal forms of human malaria, is exposed to radically different environments and stress factors during its complex lifecycle. In any organism, Hsp70 chaperones are typically associated with tolerance to stress. We therefore reasoned that inhibition of P. falciparum Hsp70 chaperones would adversely affect parasite homeostasis. To test this hypothesis, we measured whether pyrimidinone-amides, a new class of Hsp70 modulators, could inhibit the replication of the pathogenic P. falciparum stages in human red blood cells. Nine compounds with IC50 values from 30 nM to 1.6 μM were identified. Each compound also altered the ATPase activity of purified P. falciparum Hsp70 in single-turnover assays, although higher concentrations of agents were required than was necessary to inhibit P. falciparum replication. Varying effects of these compounds on Hsp70s from other organisms were also observed. Together, our data indicate that pyrimidinone-amides constitute a novel class of anti-malarial agents.

KW - ATPase

KW - Hsp40

KW - Hsp70

KW - J domain

KW - Molecular chaperone

KW - Pyrimidinone

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M3 - Article

C2 - 19195901

AN - SCOPUS:60249092974

SN - 0968-0896

VL - 17

SP - 1527

EP - 1533

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 4

ER -

Select pyrimidinones inhibit the propagation of the malarial parasite, Plasmodium falciparum

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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