Plasmepsin inhibitory activity and structure-guided optimization of a potent hydroxyethylamine-based antimalarial hit

Kristaps Jaudzems; Kaspars Tars; Gundars Maurops; Natalija Ivdra; Martins Otikovs; Janis Leitans; Iveta Kanepe-Lapsa; Ilona Domraceva; Ilze Mutule; Peteris Trapencieris; Michael J. Blackman; Aigars Jirgensons

doi:10.1021/ml4004952

Plasmepsin inhibitory activity and structure-guided optimization of a potent hydroxyethylamine-based antimalarial hit

Kristaps Jaudzems
, Kaspars Tars
, Gundars Maurops
, Natalija Ivdra
, Martins Otikovs
, Janis Leitans
, Iveta Kanepe-Lapsa
, Ilona Domraceva
, Ilze Mutule
, Peteris Trapencieris
, Michael J. Blackman
, Aigars Jirgensons^*

^*Corresponding author for this work

Latvian Institute of Organic Synthesis
Medical Research Council

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

53 Citations (Scopus)

Abstract

Antimalarial hit 1SR (TCMDC-134674) identified in a GlaxoSmithKline cell based screening campaign was evaluated for inhibitory activity against the digestive vacuole plasmepsins (Plm I, II, and IV). It was found to be a potent Plm IV inhibitor with no selectivity over Cathepsin D. A cocrystal structure of 1SR bound to Plm II was solved, providing structural insight for the design of more potent and selective analogues. Structure-guided optimization led to the identification of structurally simplified analogues 17 and 18 as low nanomolar inhibitors of both, plasmepsin Plm IV activity and P. falciparum growth in erythrocytes.

Original language	English
Pages (from-to)	373-377
Number of pages	5
Journal	ACS Medicinal Chemistry Letters
Volume	5
Issue number	4
DOIs	https://doi.org/10.1021/ml4004952
Publication status	Published - 10 Apr 2014
Externally published	Yes

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

Cathepsin D
Malaria
Plasmodium falciparum
hydroxyethylamine
inhibition
plasmepsins
structure-guided optimization

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10.1021/ml4004952

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Jaudzems, K., Tars, K., Maurops, G., Ivdra, N., Otikovs, M., Leitans, J., Kanepe-Lapsa, I., Domraceva, I., Mutule, I., Trapencieris, P., Blackman, M. J., & Jirgensons, A. (2014). Plasmepsin inhibitory activity and structure-guided optimization of a potent hydroxyethylamine-based antimalarial hit. ACS Medicinal Chemistry Letters, 5(4), 373-377. https://doi.org/10.1021/ml4004952

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title = "Plasmepsin inhibitory activity and structure-guided optimization of a potent hydroxyethylamine-based antimalarial hit",

abstract = "Antimalarial hit 1SR (TCMDC-134674) identified in a GlaxoSmithKline cell based screening campaign was evaluated for inhibitory activity against the digestive vacuole plasmepsins (Plm I, II, and IV). It was found to be a potent Plm IV inhibitor with no selectivity over Cathepsin D. A cocrystal structure of 1SR bound to Plm II was solved, providing structural insight for the design of more potent and selective analogues. Structure-guided optimization led to the identification of structurally simplified analogues 17 and 18 as low nanomolar inhibitors of both, plasmepsin Plm IV activity and P. falciparum growth in erythrocytes.",

keywords = "Cathepsin D, Malaria, Plasmodium falciparum, hydroxyethylamine, inhibition, plasmepsins, structure-guided optimization",

author = "Kristaps Jaudzems and Kaspars Tars and Gundars Maurops and Natalija Ivdra and Martins Otikovs and Janis Leitans and Iveta Kanepe-Lapsa and Ilona Domraceva and Ilze Mutule and Peteris Trapencieris and Blackman, \{Michael J.\} and Aigars Jirgensons",

year = "2014",

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doi = "10.1021/ml4004952",

language = "English",

volume = "5",

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journal = "ACS Medicinal Chemistry Letters",

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Jaudzems, K , Tars, K, Maurops, G, Ivdra, N, Otikovs, M, Leitans, J, Kanepe-Lapsa, I, Domraceva, I, Mutule, I, Trapencieris, P, Blackman, MJ & Jirgensons, A 2014, 'Plasmepsin inhibitory activity and structure-guided optimization of a potent hydroxyethylamine-based antimalarial hit', ACS Medicinal Chemistry Letters, vol. 5, no. 4, pp. 373-377. https://doi.org/10.1021/ml4004952

TY - JOUR

T1 - Plasmepsin inhibitory activity and structure-guided optimization of a potent hydroxyethylamine-based antimalarial hit

AU - Jaudzems, Kristaps

AU - Tars, Kaspars

AU - Maurops, Gundars

AU - Ivdra, Natalija

AU - Otikovs, Martins

AU - Leitans, Janis

AU - Kanepe-Lapsa, Iveta

AU - Domraceva, Ilona

AU - Mutule, Ilze

AU - Trapencieris, Peteris

AU - Blackman, Michael J.

AU - Jirgensons, Aigars

PY - 2014/4/10

Y1 - 2014/4/10

N2 - Antimalarial hit 1SR (TCMDC-134674) identified in a GlaxoSmithKline cell based screening campaign was evaluated for inhibitory activity against the digestive vacuole plasmepsins (Plm I, II, and IV). It was found to be a potent Plm IV inhibitor with no selectivity over Cathepsin D. A cocrystal structure of 1SR bound to Plm II was solved, providing structural insight for the design of more potent and selective analogues. Structure-guided optimization led to the identification of structurally simplified analogues 17 and 18 as low nanomolar inhibitors of both, plasmepsin Plm IV activity and P. falciparum growth in erythrocytes.

AB - Antimalarial hit 1SR (TCMDC-134674) identified in a GlaxoSmithKline cell based screening campaign was evaluated for inhibitory activity against the digestive vacuole plasmepsins (Plm I, II, and IV). It was found to be a potent Plm IV inhibitor with no selectivity over Cathepsin D. A cocrystal structure of 1SR bound to Plm II was solved, providing structural insight for the design of more potent and selective analogues. Structure-guided optimization led to the identification of structurally simplified analogues 17 and 18 as low nanomolar inhibitors of both, plasmepsin Plm IV activity and P. falciparum growth in erythrocytes.

KW - Cathepsin D

KW - Malaria

KW - Plasmodium falciparum

KW - hydroxyethylamine

KW - inhibition

KW - plasmepsins

KW - structure-guided optimization

UR - https://www.scopus.com/pages/publications/84898030031

U2 - 10.1021/ml4004952

DO - 10.1021/ml4004952

M3 - Article

AN - SCOPUS:84898030031

SN - 1948-5875

VL - 5

SP - 373

EP - 377

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 4

ER -

Plasmepsin inhibitory activity and structure-guided optimization of a potent hydroxyethylamine-based antimalarial hit

Abstract

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Keywords

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