Spiroindolones, a potent compound class for the treatment of malaria

Matthias Rottmann; Case McNamara; Bryan K.S. Yeung; Marcus C.S. Lee; Bin Zou; Bruce Russell; Patrick Seitz; David M. Plouffe; Neekesh V. Dharia; Jocelyn Tan; Steven B. Cohen; Kathryn R. Spencer; Gonzalo E. González-Páez; Suresh B. Lakshminarayana; Anne Goh; Rossarin Suwanarusk; Timothy Jegla; Esther K. Schmitt; Hans-Peter Beck; Reto Brun; Francois Nosten; Laurent Renia; Veronique Dartois; Thomas H. Keller; David A. Fidock; Elizabeth A. Winzeler; Thierry T. Diagana

doi:10.1126/science.1193225

Spiroindolones, a potent compound class for the treatment of malaria

Matthias Rottmann, Case McNamara, Bryan K.S. Yeung, Marcus C.S. Lee, Bin Zou, Bruce Russell, Patrick Seitz, David M. Plouffe, Neekesh V. Dharia, Jocelyn Tan, Steven B. Cohen, Kathryn R. Spencer, Gonzalo E. González-Páez, Suresh B. Lakshminarayana, Anne Goh, Rossarin Suwanarusk, Timothy Jegla, Esther K. Schmitt, Hans-Peter Beck, Reto BrunFrancois Nosten, Laurent Renia, Veronique Dartois, Thomas H. Keller, David A. Fidock, Elizabeth A. Winzeler (Lead / Corresponding author), Thierry T. Diagana (Lead / Corresponding author)

Biological Chemistry and Drug Discovery

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

1056 Citations (Scopus)

Abstract

Recent reports of increased tolerance to artemisinin derivatives - the most recently adopted class of antimalarials - have prompted a need for new treatments. The spirotetrahydro-β-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.

Original language	English
Pages (from-to)	1175-1180
Number of pages	6
Journal	Science
Volume	329
Issue number	5996
DOIs	https://doi.org/10.1126/science.1193225
Publication status	Published - 3 Sept 2010

ASJC Scopus subject areas

General

UN SDGs

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

Access to Document

10.1126/science.1193225

Cite this

Rottmann, M., McNamara, C., Yeung, B. K. S., Lee, M. C. S., Zou, B., Russell, B., Seitz, P., Plouffe, D. M., Dharia, N. V., Tan, J., Cohen, S. B., Spencer, K. R., González-Páez, G. E., Lakshminarayana, S. B., Goh, A., Suwanarusk, R., Jegla, T., Schmitt, E. K., Beck, H.-P., ... Diagana, T. T. (2010). Spiroindolones, a potent compound class for the treatment of malaria. Science, 329(5996), 1175-1180. https://doi.org/10.1126/science.1193225

@article{12fc21dc870b4223a5ba18eaa66bd614,

title = "Spiroindolones, a potent compound class for the treatment of malaria",

abstract = "Recent reports of increased tolerance to artemisinin derivatives - the most recently adopted class of antimalarials - have prompted a need for new treatments. The spirotetrahydro-β-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.",

author = "Matthias Rottmann and Case McNamara and Yeung, {Bryan K.S.} and Lee, {Marcus C.S.} and Bin Zou and Bruce Russell and Patrick Seitz and Plouffe, {David M.} and Dharia, {Neekesh V.} and Jocelyn Tan and Cohen, {Steven B.} and Spencer, {Kathryn R.} and Gonz{\'a}lez-P{\'a}ez, {Gonzalo E.} and Lakshminarayana, {Suresh B.} and Anne Goh and Rossarin Suwanarusk and Timothy Jegla and Schmitt, {Esther K.} and Hans-Peter Beck and Reto Brun and Francois Nosten and Laurent Renia and Veronique Dartois and Keller, {Thomas H.} and Fidock, {David A.} and Winzeler, {Elizabeth A.} and Diagana, {Thierry T.}",

year = "2010",

month = sep,

day = "3",

doi = "10.1126/science.1193225",

language = "English",

volume = "329",

pages = "1175--1180",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "5996",

}

Rottmann, M, McNamara, C, Yeung, BKS, Lee, MCS, Zou, B, Russell, B, Seitz, P, Plouffe, DM, Dharia, NV, Tan, J, Cohen, SB, Spencer, KR, González-Páez, GE, Lakshminarayana, SB, Goh, A, Suwanarusk, R, Jegla, T, Schmitt, EK, Beck, H-P, Brun, R, Nosten, F, Renia, L, Dartois, V, Keller, TH, Fidock, DA, Winzeler, EA & Diagana, TT 2010, 'Spiroindolones, a potent compound class for the treatment of malaria', Science, vol. 329, no. 5996, pp. 1175-1180. https://doi.org/10.1126/science.1193225

TY - JOUR

T1 - Spiroindolones, a potent compound class for the treatment of malaria

AU - Rottmann, Matthias

AU - McNamara, Case

AU - Yeung, Bryan K.S.

AU - Lee, Marcus C.S.

AU - Zou, Bin

AU - Russell, Bruce

AU - Seitz, Patrick

AU - Plouffe, David M.

AU - Dharia, Neekesh V.

AU - Tan, Jocelyn

AU - Cohen, Steven B.

AU - Spencer, Kathryn R.

AU - González-Páez, Gonzalo E.

AU - Lakshminarayana, Suresh B.

AU - Goh, Anne

AU - Suwanarusk, Rossarin

AU - Jegla, Timothy

AU - Schmitt, Esther K.

AU - Beck, Hans-Peter

AU - Brun, Reto

AU - Nosten, Francois

AU - Renia, Laurent

AU - Dartois, Veronique

AU - Keller, Thomas H.

AU - Fidock, David A.

AU - Winzeler, Elizabeth A.

AU - Diagana, Thierry T.

PY - 2010/9/3

Y1 - 2010/9/3

N2 - Recent reports of increased tolerance to artemisinin derivatives - the most recently adopted class of antimalarials - have prompted a need for new treatments. The spirotetrahydro-β-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.

AB - Recent reports of increased tolerance to artemisinin derivatives - the most recently adopted class of antimalarials - have prompted a need for new treatments. The spirotetrahydro-β-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.

UR - http://www.scopus.com/inward/record.url?scp=77956280420&partnerID=8YFLogxK

U2 - 10.1126/science.1193225

DO - 10.1126/science.1193225

M3 - Article

C2 - 20813948

AN - SCOPUS:77956280420

SN - 0036-8075

VL - 329

SP - 1175

EP - 1180

JO - Science

JF - Science

IS - 5996

ER -

Spiroindolones, a potent compound class for the treatment of malaria

Abstract

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this