Antimalarial activity of tetrahydro-β-carbolines targeting the ATP binding pocket of the Plasmodium falciparum heat shock 90 protein

Scott Eagon; Jared T. Hammill; Jordan Bach; Nikalet Everson; Tyler A. Sisley; Michael J. Walls; Sierra Durham; Dylan R. Pillai; Mofolusho O. Falade; Amy L. Rice; Joshua J. Kimball; Horacio Lazaro; Celine DiBernardo; R. Kiplin Guy

doi:10.1016/j.bmcl.2020.127502

Antimalarial activity of tetrahydro-β-carbolines targeting the ATP binding pocket of the Plasmodium falciparum heat shock 90 protein

Scott Eagon, Jared T. Hammill, Jordan Bach, Nikalet Everson, Tyler A. Sisley, Michael J. Walls, Sierra Durham, Dylan R. Pillai, Mofolusho O. Falade, Amy L. Rice, Joshua J. Kimball, Horacio Lazaro, Celine DiBernardo, R. Kiplin Guy

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

11 Citations (SciVal)

Abstract

A series of tetrahydro-β-carboline derivatives of a lead compound known to target the heat shock 90 protein of Plasmodium falciparum were synthesized and assayed for both potency against the parasite and toxicity against a human cell line. Using a rationalized structure based design strategy, a new lead compound with a potency two orders of magnitude greater than the original lead compound was found. Additional modeling of this new lead compound suggests multiple avenues to further increase potency against this target, potentially paving the path for a therapeutic with a mode of action different than any current clinical treatment.

Original language	English
Article number	127502
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	30
Issue number	21
DOIs	https://doi.org/10.1016/j.bmcl.2020.127502
State	Published - Nov 1 2020

Bibliographical note

Publisher Copyright:
© 2020 Elsevier Ltd

Keywords

Malaria
Plasmodium falciparum
Structure activity relationship
Structure based design
Tetrahydro-β-carbolines

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.bmcl.2020.127502

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Eagon, S., Hammill, J. T., Bach, J., Everson, N., Sisley, T. A., Walls, M. J., Durham, S., Pillai, D. R., Falade, M. O., Rice, A. L., Kimball, J. J., Lazaro, H., DiBernardo, C., & Kiplin Guy, R. (2020). Antimalarial activity of tetrahydro-β-carbolines targeting the ATP binding pocket of the Plasmodium falciparum heat shock 90 protein. Bioorganic and Medicinal Chemistry Letters, 30(21), Article 127502. https://doi.org/10.1016/j.bmcl.2020.127502

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abstract = "A series of tetrahydro-β-carboline derivatives of a lead compound known to target the heat shock 90 protein of Plasmodium falciparum were synthesized and assayed for both potency against the parasite and toxicity against a human cell line. Using a rationalized structure based design strategy, a new lead compound with a potency two orders of magnitude greater than the original lead compound was found. Additional modeling of this new lead compound suggests multiple avenues to further increase potency against this target, potentially paving the path for a therapeutic with a mode of action different than any current clinical treatment.",

keywords = "Malaria, Plasmodium falciparum, Structure activity relationship, Structure based design, Tetrahydro-β-carbolines",

author = "Scott Eagon and Hammill, {Jared T.} and Jordan Bach and Nikalet Everson and Sisley, {Tyler A.} and Walls, {Michael J.} and Sierra Durham and Pillai, {Dylan R.} and Falade, {Mofolusho O.} and Rice, {Amy L.} and Kimball, {Joshua J.} and Horacio Lazaro and Celine DiBernardo and {Kiplin Guy}, R.",

note = "Publisher Copyright: {\textcopyright} 2020 Elsevier Ltd",

year = "2020",

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doi = "10.1016/j.bmcl.2020.127502",

language = "English",

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Eagon, S, Hammill, JT, Bach, J, Everson, N, Sisley, TA, Walls, MJ, Durham, S, Pillai, DR, Falade, MO, Rice, AL, Kimball, JJ, Lazaro, H, DiBernardo, C & Kiplin Guy, R 2020, 'Antimalarial activity of tetrahydro-β-carbolines targeting the ATP binding pocket of the Plasmodium falciparum heat shock 90 protein', Bioorganic and Medicinal Chemistry Letters, vol. 30, no. 21, 127502. https://doi.org/10.1016/j.bmcl.2020.127502

TY - JOUR

T1 - Antimalarial activity of tetrahydro-β-carbolines targeting the ATP binding pocket of the Plasmodium falciparum heat shock 90 protein

AU - Eagon, Scott

AU - Hammill, Jared T.

AU - Bach, Jordan

AU - Everson, Nikalet

AU - Sisley, Tyler A.

AU - Walls, Michael J.

AU - Durham, Sierra

AU - Pillai, Dylan R.

AU - Falade, Mofolusho O.

AU - Rice, Amy L.

AU - Kimball, Joshua J.

AU - Lazaro, Horacio

AU - DiBernardo, Celine

AU - Kiplin Guy, R.

PY - 2020/11/1

Y1 - 2020/11/1

N2 - A series of tetrahydro-β-carboline derivatives of a lead compound known to target the heat shock 90 protein of Plasmodium falciparum were synthesized and assayed for both potency against the parasite and toxicity against a human cell line. Using a rationalized structure based design strategy, a new lead compound with a potency two orders of magnitude greater than the original lead compound was found. Additional modeling of this new lead compound suggests multiple avenues to further increase potency against this target, potentially paving the path for a therapeutic with a mode of action different than any current clinical treatment.

AB - A series of tetrahydro-β-carboline derivatives of a lead compound known to target the heat shock 90 protein of Plasmodium falciparum were synthesized and assayed for both potency against the parasite and toxicity against a human cell line. Using a rationalized structure based design strategy, a new lead compound with a potency two orders of magnitude greater than the original lead compound was found. Additional modeling of this new lead compound suggests multiple avenues to further increase potency against this target, potentially paving the path for a therapeutic with a mode of action different than any current clinical treatment.

KW - Malaria

KW - Plasmodium falciparum

KW - Structure activity relationship

KW - Structure based design

KW - Tetrahydro-β-carbolines

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U2 - 10.1016/j.bmcl.2020.127502

DO - 10.1016/j.bmcl.2020.127502

M3 - Article

C2 - 32822760

AN - SCOPUS:85089795315

SN - 0960-894X

VL - 30

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 21

M1 - 127502

ER -

Antimalarial activity of tetrahydro-β-carbolines targeting the ATP binding pocket of the Plasmodium falciparum heat shock 90 protein

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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