Chemical genetics of Plasmodium falciparum

W. Armand Guiguemde; Anang A. Shelat; David Bouck; Sandra Duffy; Gregory J. Crowther; Paul H. Davis; David C. Smithson; Michele Connelly; Julie Clark; Fangyi Zhu; María B. Jiménez-Díaz; María S. Martinez; Emily B. Wilson; Abhai K. Tripathi; Jiri Gut; Elizabeth R. Sharlow; Ian Bathurst; Farah El Mazouni; Joseph W. Fowble; Isaac Forquer; Paula L. McGinley; Steve Castro; Iñigo Angulo-Barturen; Santiago Ferrer; Philip J. Rosenthal; Joseph L. Derisi; David J. Sullivan; John S. Lazo; David S. Roos; Michael K. Riscoe; Margaret A. Phillips; Pradipsinh K. Rathod; Wesley C. Van Voorhis; Vicky M. Avery; R. Kiplin Guy

doi:10.1038/nature09099

Chemical genetics of Plasmodium falciparum

W. Armand Guiguemde, Anang A. Shelat, David Bouck, Sandra Duffy, Gregory J. Crowther, Paul H. Davis, David C. Smithson, Michele Connelly, Julie Clark, Fangyi Zhu, María B. Jiménez-Díaz, María S. Martinez, Emily B. Wilson, Abhai K. Tripathi, Jiri Gut, Elizabeth R. Sharlow, Ian Bathurst, Farah El Mazouni, Joseph W. Fowble, Isaac ForquerPaula L. McGinley, Steve Castro, Iñigo Angulo-Barturen, Santiago Ferrer, Philip J. Rosenthal, Joseph L. Derisi, David J. Sullivan, John S. Lazo, David S. Roos, Michael K. Riscoe, Margaret A. Phillips, Pradipsinh K. Rathod, Wesley C. Van Voorhis, Vicky M. Avery, R. Kiplin Guy

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Abstract

Malaria caused by Plasmodium falciparum is a disease that is responsible for 880,000 deaths per year worldwide. Vaccine development has proved difficult and resistance has emerged for most antimalarial drugs. To discover new antimalarial chemotypes, we have used a phenotypic forward chemical genetic approach to assay 309,474 chemicals. Here we disclose structures and biological activity of the entire libraryĝ€"many of which showed potent in vitro activity against drug-resistant P. falciparum strainsĝ€" and detailed profiling of 172 representative candidates. A reverse chemical genetic study identified 19 new inhibitors of 4 validated drug targets and 15 novel binders among 61 malarial proteins. Phylochemogenetic profiling in several organisms revealed similarities between Toxoplasma gondii and mammalian cell lines and dissimilarities between P. falciparum and related protozoans. One exemplar compound displayed efficacy in a murine model. Our findings provide the scientific community with new starting points for malaria drug discovery.

Original language	English
Pages (from-to)	311-315
Number of pages	5
Journal	Nature
Volume	465
Issue number	7296
DOIs	https://doi.org/10.1038/nature09099
State	Published - May 20 2010

Bibliographical note

Funding Information:
Acknowledgements This work was supported by the American Lebanese Syrian Associated Charities (ALSAC) and St Jude Children’s Research Hospital (SJCRH, R.K.G.), the Medicines for Malaria Venture (W.C.V.V. and V.M.A.), National Institute of Allergy and Infectious Diseases (AI772682 (P.H.D.), AI075517 (R.K.G.), AI067921 (W.C.V.V.) and AI080625 (W.C.V.V.), AI28724 (D.S.R.), AI53862 (J.L.D.), AI35707 (P.J.R.), AI053680 (M.A.P. and P.K.R.), AI075594 (M.A.P., P.K.R. and I.B.), AI082617 (P.K.R.) and AI045774 (D.J.S.)), the National Cancer Institute (CA78039 (J.S.L.)), the Welch Foundation (I-1257 (M.A.P.)), the Doris Duke Charitable Foundation (P.J.R.), and the Ellison Medical Foundation (D.S.R.). We acknowledge A. B. Vaidya for providing the parasite strain D10_yDHOD. We acknowledge M. Sigal for assistance in the early leads project coordination, the SJCRH High Throughput Screening Center, particularly J. Cui; the SJCRH Lead Discovery Informatics Center, and the SJCRH High Throughput Analytical Chemistry Center, particularly C. Nelson and A. Lemoff; at UW, F. Buckner, W. Hol and A. Napuli (AI067921, W. Hol); S. Wei and W. Hao in the UT Southwestern HTS Center; and the Australian Red Cross Blood Service for the provision of O1 erythrocytes to Griffith University.

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Guiguemde, W. A., Shelat, A. A., Bouck, D., Duffy, S., Crowther, G. J., Davis, P. H., Smithson, D. C., Connelly, M., Clark, J., Zhu, F., Jiménez-Díaz, M. B., Martinez, M. S., Wilson, E. B., Tripathi, A. K., Gut, J., Sharlow, E. R., Bathurst, I., Mazouni, F. E., Fowble, J. W., ... Guy, R. K. (2010). Chemical genetics of Plasmodium falciparum. Nature, 465(7296), 311-315. https://doi.org/10.1038/nature09099

@article{a257d965100e4fd5b8a6da46c916df77,

title = "Chemical genetics of Plasmodium falciparum",

abstract = "Malaria caused by Plasmodium falciparum is a disease that is responsible for 880,000 deaths per year worldwide. Vaccine development has proved difficult and resistance has emerged for most antimalarial drugs. To discover new antimalarial chemotypes, we have used a phenotypic forward chemical genetic approach to assay 309,474 chemicals. Here we disclose structures and biological activity of the entire libraryĝ€{"}many of which showed potent in vitro activity against drug-resistant P. falciparum strainsĝ€{"} and detailed profiling of 172 representative candidates. A reverse chemical genetic study identified 19 new inhibitors of 4 validated drug targets and 15 novel binders among 61 malarial proteins. Phylochemogenetic profiling in several organisms revealed similarities between Toxoplasma gondii and mammalian cell lines and dissimilarities between P. falciparum and related protozoans. One exemplar compound displayed efficacy in a murine model. Our findings provide the scientific community with new starting points for malaria drug discovery.",

author = "Guiguemde, {W. Armand} and Shelat, {Anang A.} and David Bouck and Sandra Duffy and Crowther, {Gregory J.} and Davis, {Paul H.} and Smithson, {David C.} and Michele Connelly and Julie Clark and Fangyi Zhu and Jim{\'e}nez-D{\'i}az, {Mar{\'i}a B.} and Martinez, {Mar{\'i}a S.} and Wilson, {Emily B.} and Tripathi, {Abhai K.} and Jiri Gut and Sharlow, {Elizabeth R.} and Ian Bathurst and Mazouni, {Farah El} and Fowble, {Joseph W.} and Isaac Forquer and McGinley, {Paula L.} and Steve Castro and I{\~n}igo Angulo-Barturen and Santiago Ferrer and Rosenthal, {Philip J.} and Derisi, {Joseph L.} and Sullivan, {David J.} and Lazo, {John S.} and Roos, {David S.} and Riscoe, {Michael K.} and Phillips, {Margaret A.} and Rathod, {Pradipsinh K.} and {Van Voorhis}, {Wesley C.} and Avery, {Vicky M.} and Guy, {R. Kiplin}",

note = "Funding Information: Acknowledgements This work was supported by the American Lebanese Syrian Associated Charities (ALSAC) and St Jude Children{\textquoteright}s Research Hospital (SJCRH, R.K.G.), the Medicines for Malaria Venture (W.C.V.V. and V.M.A.), National Institute of Allergy and Infectious Diseases (AI772682 (P.H.D.), AI075517 (R.K.G.), AI067921 (W.C.V.V.) and AI080625 (W.C.V.V.), AI28724 (D.S.R.), AI53862 (J.L.D.), AI35707 (P.J.R.), AI053680 (M.A.P. and P.K.R.), AI075594 (M.A.P., P.K.R. and I.B.), AI082617 (P.K.R.) and AI045774 (D.J.S.)), the National Cancer Institute (CA78039 (J.S.L.)), the Welch Foundation (I-1257 (M.A.P.)), the Doris Duke Charitable Foundation (P.J.R.), and the Ellison Medical Foundation (D.S.R.). We acknowledge A. B. Vaidya for providing the parasite strain D10_yDHOD. We acknowledge M. Sigal for assistance in the early leads project coordination, the SJCRH High Throughput Screening Center, particularly J. Cui; the SJCRH Lead Discovery Informatics Center, and the SJCRH High Throughput Analytical Chemistry Center, particularly C. Nelson and A. Lemoff; at UW, F. Buckner, W. Hol and A. Napuli (AI067921, W. Hol); S. Wei and W. Hao in the UT Southwestern HTS Center; and the Australian Red Cross Blood Service for the provision of O1 erythrocytes to Griffith University.",

year = "2010",

month = may,

day = "20",

doi = "10.1038/nature09099",

language = "English",

volume = "465",

pages = "311--315",

number = "7296",

}

Guiguemde, WA, Shelat, AA, Bouck, D, Duffy, S, Crowther, GJ, Davis, PH, Smithson, DC, Connelly, M, Clark, J, Zhu, F, Jiménez-Díaz, MB, Martinez, MS, Wilson, EB, Tripathi, AK, Gut, J, Sharlow, ER, Bathurst, I, Mazouni, FE, Fowble, JW, Forquer, I, McGinley, PL, Castro, S, Angulo-Barturen, I, Ferrer, S, Rosenthal, PJ, Derisi, JL, Sullivan, DJ, Lazo, JS, Roos, DS, Riscoe, MK, Phillips, MA, Rathod, PK, Van Voorhis, WC, Avery, VM & Guy, RK 2010, 'Chemical genetics of Plasmodium falciparum', Nature, vol. 465, no. 7296, pp. 311-315. https://doi.org/10.1038/nature09099

TY - JOUR

T1 - Chemical genetics of Plasmodium falciparum

AU - Guiguemde, W. Armand

AU - Shelat, Anang A.

AU - Bouck, David

AU - Duffy, Sandra

AU - Crowther, Gregory J.

AU - Davis, Paul H.

AU - Smithson, David C.

AU - Connelly, Michele

AU - Clark, Julie

AU - Zhu, Fangyi

AU - Jiménez-Díaz, María B.

AU - Martinez, María S.

AU - Wilson, Emily B.

AU - Tripathi, Abhai K.

AU - Gut, Jiri

AU - Sharlow, Elizabeth R.

AU - Bathurst, Ian

AU - Mazouni, Farah El

AU - Fowble, Joseph W.

AU - Forquer, Isaac

AU - McGinley, Paula L.

AU - Castro, Steve

AU - Angulo-Barturen, Iñigo

AU - Ferrer, Santiago

AU - Rosenthal, Philip J.

AU - Derisi, Joseph L.

AU - Sullivan, David J.

AU - Lazo, John S.

AU - Roos, David S.

AU - Riscoe, Michael K.

AU - Phillips, Margaret A.

AU - Rathod, Pradipsinh K.

AU - Van Voorhis, Wesley C.

AU - Avery, Vicky M.

AU - Guy, R. Kiplin

N1 - Funding Information: Acknowledgements This work was supported by the American Lebanese Syrian Associated Charities (ALSAC) and St Jude Children’s Research Hospital (SJCRH, R.K.G.), the Medicines for Malaria Venture (W.C.V.V. and V.M.A.), National Institute of Allergy and Infectious Diseases (AI772682 (P.H.D.), AI075517 (R.K.G.), AI067921 (W.C.V.V.) and AI080625 (W.C.V.V.), AI28724 (D.S.R.), AI53862 (J.L.D.), AI35707 (P.J.R.), AI053680 (M.A.P. and P.K.R.), AI075594 (M.A.P., P.K.R. and I.B.), AI082617 (P.K.R.) and AI045774 (D.J.S.)), the National Cancer Institute (CA78039 (J.S.L.)), the Welch Foundation (I-1257 (M.A.P.)), the Doris Duke Charitable Foundation (P.J.R.), and the Ellison Medical Foundation (D.S.R.). We acknowledge A. B. Vaidya for providing the parasite strain D10_yDHOD. We acknowledge M. Sigal for assistance in the early leads project coordination, the SJCRH High Throughput Screening Center, particularly J. Cui; the SJCRH Lead Discovery Informatics Center, and the SJCRH High Throughput Analytical Chemistry Center, particularly C. Nelson and A. Lemoff; at UW, F. Buckner, W. Hol and A. Napuli (AI067921, W. Hol); S. Wei and W. Hao in the UT Southwestern HTS Center; and the Australian Red Cross Blood Service for the provision of O1 erythrocytes to Griffith University.

PY - 2010/5/20

Y1 - 2010/5/20

N2 - Malaria caused by Plasmodium falciparum is a disease that is responsible for 880,000 deaths per year worldwide. Vaccine development has proved difficult and resistance has emerged for most antimalarial drugs. To discover new antimalarial chemotypes, we have used a phenotypic forward chemical genetic approach to assay 309,474 chemicals. Here we disclose structures and biological activity of the entire libraryĝ€"many of which showed potent in vitro activity against drug-resistant P. falciparum strainsĝ€" and detailed profiling of 172 representative candidates. A reverse chemical genetic study identified 19 new inhibitors of 4 validated drug targets and 15 novel binders among 61 malarial proteins. Phylochemogenetic profiling in several organisms revealed similarities between Toxoplasma gondii and mammalian cell lines and dissimilarities between P. falciparum and related protozoans. One exemplar compound displayed efficacy in a murine model. Our findings provide the scientific community with new starting points for malaria drug discovery.

AB - Malaria caused by Plasmodium falciparum is a disease that is responsible for 880,000 deaths per year worldwide. Vaccine development has proved difficult and resistance has emerged for most antimalarial drugs. To discover new antimalarial chemotypes, we have used a phenotypic forward chemical genetic approach to assay 309,474 chemicals. Here we disclose structures and biological activity of the entire libraryĝ€"many of which showed potent in vitro activity against drug-resistant P. falciparum strainsĝ€" and detailed profiling of 172 representative candidates. A reverse chemical genetic study identified 19 new inhibitors of 4 validated drug targets and 15 novel binders among 61 malarial proteins. Phylochemogenetic profiling in several organisms revealed similarities between Toxoplasma gondii and mammalian cell lines and dissimilarities between P. falciparum and related protozoans. One exemplar compound displayed efficacy in a murine model. Our findings provide the scientific community with new starting points for malaria drug discovery.

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U2 - 10.1038/nature09099

DO - 10.1038/nature09099

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AN - SCOPUS:77952718950

SN - 0028-0836

VL - 465

SP - 311

EP - 315

JO - Nature

JF - Nature

IS - 7296

ER -

Chemical genetics of Plasmodium falciparum

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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