A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue.

Ebere Sonoiki; Caroline L. Ng; Marcus C. S. Lee; Denghui Guo; Yong-Kang Zhang; Yasheen Zhou; M. R. K. Alley; Vida Ahyong; Laura M. Sanz; Maria Jose Lafuente-Monasterio; Chen Dong; Patrick G Schupp; Jiri Gut; Jenny Legac; Roland A. Cooper; Francisco-Javier Gamo; Joseph DeRisi; Yvonne R. Freund; David A. Fidock; Philip J. Rosenthal

doi:10.1038/ncomms14574

A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue.

Ebere Sonoiki, Caroline L. Ng, Marcus C. S. Lee, Denghui Guo, Yong-Kang Zhang, Yasheen Zhou, M. R. K. Alley, Vida Ahyong, Laura M. Sanz, Maria Jose Lafuente-Monasterio, Chen Dong, Patrick G Schupp, Jiri Gut, Jenny Legac, Roland A. Cooper, Francisco-Javier Gamo, Joseph DeRisi, Yvonne R. Freund, David A. Fidock, Philip J. Rosenthal

Department of Natural Sciences and Mathematics

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

Abstract

Benzoxaboroles are effective against bacterial, fungal and protozoan pathogens. We report potent activity of the benzoxaborole AN3661 against Plasmodium falciparum laboratory-adapted strains (mean IC50 32 nM), Ugandan field isolates (mean ex vivo IC50 64 nM), and murine P. berghei and P. falciparum infections (day 4 ED90 0.34 and 0.57 mg kg-1, respectively). Multiple P. falciparum lines selected in vitro for resistance to AN3661 harboured point mutations in pfcpsf3, which encodes a homologue of mammalian cleavage and polyadenylation specificity factor subunit 3 (CPSF-73 or CPSF3). CRISPR-Cas9-mediated introduction of pfcpsf3 mutations into parental lines recapitulated AN3661 resistance. PfCPSF3 homology models placed these mutations in the active site, where AN3661 is predicted to bind. Transcripts for three trophozoite-expressed genes were lost in AN3661-treated trophozoites, which was not observed in parasites selected or engineered for AN3661 resistance. Our results identify the pre-mRNA processing factor PfCPSF3 as a promising antimalarial drug target.

Original language	American English
Article number	14574
Pages (from-to)	14574
Journal	Default journal
Volume	8
DOIs	https://doi.org/10.1038/ncomms14574
State	Published - Mar 6 2017

Funding

This work was supported by the National Institutes of Health (AI095324 and AI103058) and the Medicines for Malaria Venture. J.D. was funded by the Howard Hughes Medical Institute.

Funders	Funder number
National Institutes of Health	AI095324, AI103058
Howard Hughes Medical Institute
Medicines for Malaria Venture

ASJC Scopus Subject Areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

Keywords

Amino Acid Sequence
Animals
Antimalarials
Boron Compounds
CRISPR-Cas Systems
Catalytic Domain
Cleavage And Polyadenylation Specificity Factor
Drug Resistance
Erythrocytes
Gene Editing
Humans
Malaria
Falciparum
Mice
Molecular Docking Simulation
Mutation
Plasmodium berghei
Plasmodium falciparum
Protein Binding
Protein Interaction Domains and Motifs
Protein Structure
Secondary
Protozoan Proteins
RNA
Messenger
Sequence Alignment
Sequence Homology
Amino Acid
Trophozoites

Disciplines

Immunology and Infectious Disease

Access to Document

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A potent antimalarial benzoxaborole targets a Plasmodium falciparFinal published version, 1.49 MBLicense: Unspecified

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Sonoiki, E., Ng, C. L., Lee, M. C. S., Guo, D., Zhang, Y.-K., Zhou, Y., Alley, M. R. K., Ahyong, V., Sanz, L. M., Lafuente-Monasterio, M. J., Dong, C., Schupp, P. G., Gut, J., Legac, J., Cooper, R. A., Gamo, F.-J., DeRisi, J., Freund, Y. R., Fidock, D. A., & Rosenthal, P. J. (2017). A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue. Default journal, 8, 14574. Article 14574. https://doi.org/10.1038/ncomms14574

Sonoiki, E, Ng, CL, Lee, MCS, Guo, D, Zhang, Y-K, Zhou, Y, Alley, MRK, Ahyong, V, Sanz, LM, Lafuente-Monasterio, MJ, Dong, C, Schupp, PG, Gut, J, Legac, J, Cooper, RA, Gamo, F-J, DeRisi, J, Freund, YR, Fidock, DA & Rosenthal, PJ 2017, 'A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue.', Default journal, vol. 8, 14574, pp. 14574. https://doi.org/10.1038/ncomms14574

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title = "A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue.",

abstract = "Benzoxaboroles are effective against bacterial, fungal and protozoan pathogens. We report potent activity of the benzoxaborole AN3661 against Plasmodium falciparum laboratory-adapted strains (mean IC50 32 nM), Ugandan field isolates (mean ex vivo IC50 64 nM), and murine P. berghei and P. falciparum infections (day 4 ED90 0.34 and 0.57 mg kg-1, respectively). Multiple P. falciparum lines selected in vitro for resistance to AN3661 harboured point mutations in pfcpsf3, which encodes a homologue of mammalian cleavage and polyadenylation specificity factor subunit 3 (CPSF-73 or CPSF3). CRISPR-Cas9-mediated introduction of pfcpsf3 mutations into parental lines recapitulated AN3661 resistance. PfCPSF3 homology models placed these mutations in the active site, where AN3661 is predicted to bind. Transcripts for three trophozoite-expressed genes were lost in AN3661-treated trophozoites, which was not observed in parasites selected or engineered for AN3661 resistance. Our results identify the pre-mRNA processing factor PfCPSF3 as a promising antimalarial drug target.",

keywords = "Amino Acid Sequence, Animals, Antimalarials, Boron Compounds, CRISPR-Cas Systems, Catalytic Domain, Cleavage And Polyadenylation Specificity Factor, Drug Resistance, Erythrocytes, Gene Editing, Humans, Malaria, Falciparum, Mice, Molecular Docking Simulation, Mutation, Plasmodium berghei, Plasmodium falciparum, Protein Binding, Protein Interaction Domains and Motifs, Protein Structure, Secondary, Protozoan Proteins, RNA, Messenger, Sequence Alignment, Sequence Homology, Amino Acid, Trophozoites",

author = "Ebere Sonoiki and Ng, \{Caroline L.\} and Lee, \{Marcus C. S.\} and Denghui Guo and Yong-Kang Zhang and Yasheen Zhou and Alley, \{M. R. K.\} and Vida Ahyong and Sanz, \{Laura M.\} and Lafuente-Monasterio, \{Maria Jose\} and Chen Dong and Schupp, \{Patrick G\} and Jiri Gut and Jenny Legac and Cooper, \{Roland A.\} and Francisco-Javier Gamo and Joseph DeRisi and Freund, \{Yvonne R.\} and Fidock, \{David A.\} and Rosenthal, \{Philip J.\}",

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AU - Sonoiki, Ebere

AU - Ng, Caroline L.

AU - Lee, Marcus C. S.

AU - Guo, Denghui

AU - Zhang, Yong-Kang

AU - Zhou, Yasheen

AU - Alley, M. R. K.

AU - Ahyong, Vida

AU - Sanz, Laura M.

AU - Lafuente-Monasterio, Maria Jose

AU - Dong, Chen

AU - Schupp, Patrick G

AU - Gut, Jiri

AU - Legac, Jenny

AU - Cooper, Roland A.

AU - Gamo, Francisco-Javier

AU - DeRisi, Joseph

AU - Freund, Yvonne R.

AU - Fidock, David A.

AU - Rosenthal, Philip J.

PY - 2017/3/6

Y1 - 2017/3/6

N2 - Benzoxaboroles are effective against bacterial, fungal and protozoan pathogens. We report potent activity of the benzoxaborole AN3661 against Plasmodium falciparum laboratory-adapted strains (mean IC50 32 nM), Ugandan field isolates (mean ex vivo IC50 64 nM), and murine P. berghei and P. falciparum infections (day 4 ED90 0.34 and 0.57 mg kg-1, respectively). Multiple P. falciparum lines selected in vitro for resistance to AN3661 harboured point mutations in pfcpsf3, which encodes a homologue of mammalian cleavage and polyadenylation specificity factor subunit 3 (CPSF-73 or CPSF3). CRISPR-Cas9-mediated introduction of pfcpsf3 mutations into parental lines recapitulated AN3661 resistance. PfCPSF3 homology models placed these mutations in the active site, where AN3661 is predicted to bind. Transcripts for three trophozoite-expressed genes were lost in AN3661-treated trophozoites, which was not observed in parasites selected or engineered for AN3661 resistance. Our results identify the pre-mRNA processing factor PfCPSF3 as a promising antimalarial drug target.

AB - Benzoxaboroles are effective against bacterial, fungal and protozoan pathogens. We report potent activity of the benzoxaborole AN3661 against Plasmodium falciparum laboratory-adapted strains (mean IC50 32 nM), Ugandan field isolates (mean ex vivo IC50 64 nM), and murine P. berghei and P. falciparum infections (day 4 ED90 0.34 and 0.57 mg kg-1, respectively). Multiple P. falciparum lines selected in vitro for resistance to AN3661 harboured point mutations in pfcpsf3, which encodes a homologue of mammalian cleavage and polyadenylation specificity factor subunit 3 (CPSF-73 or CPSF3). CRISPR-Cas9-mediated introduction of pfcpsf3 mutations into parental lines recapitulated AN3661 resistance. PfCPSF3 homology models placed these mutations in the active site, where AN3661 is predicted to bind. Transcripts for three trophozoite-expressed genes were lost in AN3661-treated trophozoites, which was not observed in parasites selected or engineered for AN3661 resistance. Our results identify the pre-mRNA processing factor PfCPSF3 as a promising antimalarial drug target.

KW - Amino Acid Sequence

KW - Animals

KW - Antimalarials

KW - Boron Compounds

KW - CRISPR-Cas Systems

KW - Catalytic Domain

KW - Cleavage And Polyadenylation Specificity Factor

KW - Drug Resistance

KW - Erythrocytes

KW - Gene Editing

KW - Humans

KW - Malaria

KW - Falciparum

KW - Mice

KW - Molecular Docking Simulation

KW - Mutation

KW - Plasmodium berghei

KW - Plasmodium falciparum

KW - Protein Binding

KW - Protein Interaction Domains and Motifs

KW - Protein Structure

KW - Secondary

KW - Protozoan Proteins

KW - RNA

KW - Messenger

KW - Sequence Alignment

KW - Sequence Homology

KW - Amino Acid

KW - Trophozoites

UR - https://scholar.dominican.edu/natural-sciences-and-mathematics-faculty-scholarship/45

U2 - 10.1038/ncomms14574

DO - 10.1038/ncomms14574

M3 - Article

C2 - 28262680

VL - 8

SP - 14574

JO - Default journal

JF - Default journal

M1 - 14574

ER -

A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue.

Abstract

Funding

ASJC Scopus Subject Areas

Keywords

Disciplines

Access to Document

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