Basis for drug selectivity of plasmepsin IX and X inhibition in Plasmodium falciparum and vivax

Anthony N. Hodder; Janni Christensen; Stephen Scally; Tony Triglia; Anna Ngo; Richard W. Birkinshaw; Brodie Bailey; Paola Favuzza; Melanie H. Dietrich; Wai Hong Tham; Peter E. Czabotar; Kym Lowes; Zhuyan Guo; Nicholas Murgolo; Manuel de Lera Ruiz; John A. McCauley; Brad E. Sleebs; David Olsen; Alan F. Cowman

doi:10.1016/j.str.2022.03.018

Basis for drug selectivity of plasmepsin IX and X inhibition in Plasmodium falciparum and vivax

Anthony N. Hodder, Janni Christensen, Stephen Scally, Tony Triglia, Anna Ngo, Richard W. Birkinshaw, Brodie Bailey, Paola Favuzza, Melanie H. Dietrich, Wai Hong Tham, Peter E. Czabotar, Kym Lowes, Zhuyan Guo, Nicholas Murgolo, Manuel de Lera Ruiz, John A. McCauley, Brad E. Sleebs, David Olsen, Alan F. Cowman^*

^*Corresponding author for this work

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

18 Citations (Scopus)

Abstract

Plasmepsins IX (PMIX) and X (PMX) are essential aspartyl proteases for Plasmodium spp. egress, invasion, and development. WM4 and WM382 inhibit PMIX and PMX in Plasmodium falciparum and P. vivax. WM4 inhibits PMX, while WM382 is a dual inhibitor of PMIX and PMX. To understand their function, we identified protein substrates. Enzyme kinetic and structural analyses identified interactions responsible for drug specificity. PMIX and PMX have similar substrate specificity; however, there are distinct differences for peptide and protein substrates. Differences in WM4 and WM382 binding for PMIX and PMX map to variations in the S' region and engagement of the active site S3 pocket. Structures of PMX reveal interactions and mechanistic detail of drug binding important for development of clinical candidates against these targets.

Original language	English
Pages (from-to)	947-961.e6
Number of pages	22
Journal	Structure
Volume	30
Issue number	7
DOIs	https://doi.org/10.1016/j.str.2022.03.018
Publication status	Published - 7 Jul 2022
Externally published	Yes

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10.1016/j.str.2022.03.018

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Hodder, A. N., Christensen, J., Scally, S., Triglia, T., Ngo, A., Birkinshaw, R. W., Bailey, B., Favuzza, P., Dietrich, M. H., Tham, W. H., Czabotar, P. E., Lowes, K., Guo, Z., Murgolo, N., Lera Ruiz, M. D., McCauley, J. A., Sleebs, B. E., Olsen, D., & Cowman, A. F. (2022). Basis for drug selectivity of plasmepsin IX and X inhibition in Plasmodium falciparum and vivax. Structure, 30(7), 947-961.e6. https://doi.org/10.1016/j.str.2022.03.018

@article{3be6e90451d24e0f951b9fbf1efbe542,

title = "Basis for drug selectivity of plasmepsin IX and X inhibition in Plasmodium falciparum and vivax",

abstract = "Plasmepsins IX (PMIX) and X (PMX) are essential aspartyl proteases for Plasmodium spp. egress, invasion, and development. WM4 and WM382 inhibit PMIX and PMX in Plasmodium falciparum and P. vivax. WM4 inhibits PMX, while WM382 is a dual inhibitor of PMIX and PMX. To understand their function, we identified protein substrates. Enzyme kinetic and structural analyses identified interactions responsible for drug specificity. PMIX and PMX have similar substrate specificity; however, there are distinct differences for peptide and protein substrates. Differences in WM4 and WM382 binding for PMIX and PMX map to variations in the S' region and engagement of the active site S3 pocket. Structures of PMX reveal interactions and mechanistic detail of drug binding important for development of clinical candidates against these targets.",

keywords = "antimalarial, aspartic protease, enzzyme kinetics, malaria, plasmepsin IX, plasmepsin X, protein-drug structure",

author = "Hodder, {Anthony N.} and Janni Christensen and Stephen Scally and Tony Triglia and Anna Ngo and Birkinshaw, {Richard W.} and Brodie Bailey and Paola Favuzza and Dietrich, {Melanie H.} and Tham, {Wai Hong} and Czabotar, {Peter E.} and Kym Lowes and Zhuyan Guo and Nicholas Murgolo and {Lera Ruiz}, {Manuel de} and McCauley, {John A.} and Sleebs, {Brad E.} and David Olsen and Cowman, {Alan F.}",

note = "Publisher Copyright: {\textcopyright} 2022",

year = "2022",

month = jul,

day = "7",

doi = "10.1016/j.str.2022.03.018",

language = "English",

volume = "30",

pages = "947--961.e6",

journal = "Structure",

issn = "0969-2126",

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number = "7",

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Hodder, AN, Christensen, J, Scally, S, Triglia, T, Ngo, A, Birkinshaw, RW, Bailey, B, Favuzza, P, Dietrich, MH, Tham, WH, Czabotar, PE, Lowes, K, Guo, Z, Murgolo, N, Lera Ruiz, MD, McCauley, JA, Sleebs, BE, Olsen, D & Cowman, AF 2022, 'Basis for drug selectivity of plasmepsin IX and X inhibition in Plasmodium falciparum and vivax', Structure, vol. 30, no. 7, pp. 947-961.e6. https://doi.org/10.1016/j.str.2022.03.018

TY - JOUR

T1 - Basis for drug selectivity of plasmepsin IX and X inhibition in Plasmodium falciparum and vivax

AU - Hodder, Anthony N.

AU - Christensen, Janni

AU - Scally, Stephen

AU - Triglia, Tony

AU - Ngo, Anna

AU - Birkinshaw, Richard W.

AU - Bailey, Brodie

AU - Favuzza, Paola

AU - Dietrich, Melanie H.

AU - Tham, Wai Hong

AU - Czabotar, Peter E.

AU - Lowes, Kym

AU - Guo, Zhuyan

AU - Murgolo, Nicholas

AU - Lera Ruiz, Manuel de

AU - McCauley, John A.

AU - Sleebs, Brad E.

AU - Olsen, David

AU - Cowman, Alan F.

PY - 2022/7/7

Y1 - 2022/7/7

N2 - Plasmepsins IX (PMIX) and X (PMX) are essential aspartyl proteases for Plasmodium spp. egress, invasion, and development. WM4 and WM382 inhibit PMIX and PMX in Plasmodium falciparum and P. vivax. WM4 inhibits PMX, while WM382 is a dual inhibitor of PMIX and PMX. To understand their function, we identified protein substrates. Enzyme kinetic and structural analyses identified interactions responsible for drug specificity. PMIX and PMX have similar substrate specificity; however, there are distinct differences for peptide and protein substrates. Differences in WM4 and WM382 binding for PMIX and PMX map to variations in the S' region and engagement of the active site S3 pocket. Structures of PMX reveal interactions and mechanistic detail of drug binding important for development of clinical candidates against these targets.

AB - Plasmepsins IX (PMIX) and X (PMX) are essential aspartyl proteases for Plasmodium spp. egress, invasion, and development. WM4 and WM382 inhibit PMIX and PMX in Plasmodium falciparum and P. vivax. WM4 inhibits PMX, while WM382 is a dual inhibitor of PMIX and PMX. To understand their function, we identified protein substrates. Enzyme kinetic and structural analyses identified interactions responsible for drug specificity. PMIX and PMX have similar substrate specificity; however, there are distinct differences for peptide and protein substrates. Differences in WM4 and WM382 binding for PMIX and PMX map to variations in the S' region and engagement of the active site S3 pocket. Structures of PMX reveal interactions and mechanistic detail of drug binding important for development of clinical candidates against these targets.

KW - antimalarial

KW - aspartic protease

KW - enzzyme kinetics

KW - malaria

KW - plasmepsin IX

KW - plasmepsin X

KW - protein-drug structure

UR - http://www.scopus.com/inward/record.url?scp=85133195351&partnerID=8YFLogxK

U2 - 10.1016/j.str.2022.03.018

DO - 10.1016/j.str.2022.03.018

M3 - Article

C2 - 35460613

AN - SCOPUS:85133195351

SN - 0969-2126

VL - 30

SP - 947-961.e6

JO - Structure

JF - Structure

IS - 7

ER -

Basis for drug selectivity of plasmepsin IX and X inhibition in Plasmodium falciparum and vivax

Abstract

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