MK-7602: a potent multi-stage dual-targeting antimalarial

Paola Favuzza; Josephine Palandri; Manuel de Lera Ruiz; Wendy Bailey; Christopher W. Boyce; Andrew Danziger; Maria V. Fawaz; Michael Kelly; Nicholas Murgolo; Jonathan A. Robbins; Marissa Vavrek; Lianyun Zhao; Zhiyu Lei; Zhuyan Guo; Kitsanapong Reaksudsan; Ryan W. J. Steel; Anthony N. Hodder; Anna Ngo; Jerzy M. Dziekan; Jennifer K. Thompson; Tony Triglia; Richard W. Birkinshaw; Jocelyn Sietsma Penington; Stephen W. Scally; Madeline G. Dans; Rachael Coyle; Nicole Sevilleno; Agnes Orban; Lionel Brice Feufack-Donfack; Jean Popovici; Marcus C. S. Lee; Anthony Papenfuss; Kym N. Lowes; Brad E. Sleebs; James S. McCarthy; John A. McCauley; Justin A. Boddey; David B. Olsen; Alan F. Cowman

doi:10.1016/j.ebiom.2025.106061

MK-7602: a potent multi-stage dual-targeting antimalarial

Paola Favuzza
, Josephine Palandri
, Manuel de Lera Ruiz
, Wendy Bailey
, Christopher W. Boyce
, Andrew Danziger
, Maria V. Fawaz
, Michael Kelly
, Nicholas Murgolo
, Jonathan A. Robbins
, Marissa Vavrek
, Lianyun Zhao
, Zhiyu Lei
, Zhuyan Guo
, Kitsanapong Reaksudsan
, Ryan W. J. Steel
, Anthony N. Hodder
, Anna Ngo
, Jerzy M. Dziekan
, Jennifer K. Thompson

Tony Triglia, Richard W. Birkinshaw, Jocelyn Sietsma Penington, Stephen W. Scally, Madeline G. Dans, Rachael Coyle, Nicole Sevilleno, Agnes Orban, Lionel Brice Feufack-Donfack, Jean Popovici, Marcus C. S. Lee, Anthony Papenfuss, Kym N. Lowes, Brad E. Sleebs, James S. McCarthy, John A. McCauley, Justin A. Boddey, David B. Olsen, Alan F. Cowman (Lead / Corresponding author)

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

Abstract

Background: The global burden of malaria remains substantial, and increasing parasite resistance to current antimalarials necessitates the development of drugs with unique mechanisms of action. This study aimed to develop and characterise a new antimalarial compound targeting Plasmodium aspartic proteases.

Methods: We conducted high-throughput screening, medicinal chemistry optimisation, and extensive in vitro and in vivo testing to develop and evaluate MK-7602, a dual inhibitor of plasmepsins IX and X.

Findings: MK-7602, a clinical candidate, acts as a dual sub-nanomolar inhibitor of plasmepsins IX and X in multiple Plasmodium species. It exhibits favourable pharmacokinetic properties and a promising safety profile. MK-7602 demonstrates activity against liver and blood life-cycle stages of the parasite and blocks transmission to mosquitoes. Importantly, it shows a high barrier to resistance development and lacks cross-resistance with Plasmodium falciparum strains resistant to other antimalarials. MK-7602 effectively inhibits both wild-type parasites and those with increased plasmepsin expression, highlighting its potential to overcome existing resistance mechanisms.

Interpretation: MK-7602 represents a new class of antimalarial for treating uncomplicated malaria with a new mechanism of action and the potential to address drug-resistant malaria. Clinical evaluation of MK-7602's activity against P. falciparum is ongoing.

Original language	English
Article number	106061
Number of pages	20
Journal	EBioMedicine
Volume	123
Early online date	5 Dec 2025
DOIs	https://doi.org/10.1016/j.ebiom.2025.106061
Publication status	Published - Jan 2026

Keywords

Antimalarial drug
Aspartic proteases
Falciparum
Malaria
Plasmepsin
Vivax

ASJC Scopus subject areas

General Medicine
General Biochemistry,Genetics and Molecular Biology

UN SDGs

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

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10.1016/j.ebiom.2025.106061Licence: CC BY-NC-ND

Final Published VersionFinal published version, 7.26 MBLicence: CC BY-NC-ND

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Favuzza, P., Palandri, J., de Lera Ruiz, M., Bailey, W., Boyce, C. W., Danziger, A., Fawaz, M. V., Kelly, M., Murgolo, N., Robbins, J. A., Vavrek, M., Zhao, L., Lei, Z., Guo, Z., Reaksudsan, K., Steel, R. W. J., Hodder, A. N., Ngo, A., Dziekan, J. M., ... Cowman, A. F. (2026). MK-7602: a potent multi-stage dual-targeting antimalarial. EBioMedicine, 123, Article 106061. https://doi.org/10.1016/j.ebiom.2025.106061

@article{cb8f0909f1b54096a16d3a92cd7534ca,

title = "MK-7602: a potent multi-stage dual-targeting antimalarial",

abstract = "Background: The global burden of malaria remains substantial, and increasing parasite resistance to current antimalarials necessitates the development of drugs with unique mechanisms of action. This study aimed to develop and characterise a new antimalarial compound targeting Plasmodium aspartic proteases.Methods: We conducted high-throughput screening, medicinal chemistry optimisation, and extensive in vitro and in vivo testing to develop and evaluate MK-7602, a dual inhibitor of plasmepsins IX and X.Findings: MK-7602, a clinical candidate, acts as a dual sub-nanomolar inhibitor of plasmepsins IX and X in multiple Plasmodium species. It exhibits favourable pharmacokinetic properties and a promising safety profile. MK-7602 demonstrates activity against liver and blood life-cycle stages of the parasite and blocks transmission to mosquitoes. Importantly, it shows a high barrier to resistance development and lacks cross-resistance with Plasmodium falciparum strains resistant to other antimalarials. MK-7602 effectively inhibits both wild-type parasites and those with increased plasmepsin expression, highlighting its potential to overcome existing resistance mechanisms.Interpretation: MK-7602 represents a new class of antimalarial for treating uncomplicated malaria with a new mechanism of action and the potential to address drug-resistant malaria. Clinical evaluation of MK-7602's activity against P. falciparum is ongoing.",

keywords = "Antimalarial drug, Aspartic proteases, Falciparum, Malaria, Plasmepsin, Vivax",

author = "Paola Favuzza and Josephine Palandri and \{de Lera Ruiz\}, Manuel and Wendy Bailey and Boyce, \{Christopher W.\} and Andrew Danziger and Fawaz, \{Maria V.\} and Michael Kelly and Nicholas Murgolo and Robbins, \{Jonathan A.\} and Marissa Vavrek and Lianyun Zhao and Zhiyu Lei and Zhuyan Guo and Kitsanapong Reaksudsan and Steel, \{Ryan W. J.\} and Hodder, \{Anthony N.\} and Anna Ngo and Dziekan, \{Jerzy M.\} and Thompson, \{Jennifer K.\} and Tony Triglia and Birkinshaw, \{Richard W.\} and Penington, \{Jocelyn Sietsma\} and Scally, \{Stephen W.\} and Dans, \{Madeline G.\} and Rachael Coyle and Nicole Sevilleno and Agnes Orban and Feufack-Donfack, \{Lionel Brice\} and Jean Popovici and Lee, \{Marcus C. S.\} and Anthony Papenfuss and Lowes, \{Kym N.\} and Sleebs, \{Brad E.\} and McCarthy, \{James S.\} and McCauley, \{John A.\} and Boddey, \{Justin A.\} and Olsen, \{David B.\} and Cowman, \{Alan F.\}",

note = "Copyright: {\textcopyright} 2025 The Author(s)",

year = "2026",

month = jan,

doi = "10.1016/j.ebiom.2025.106061",

language = "English",

volume = "123",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier",

}

Favuzza, P, Palandri, J, de Lera Ruiz, M, Bailey, W, Boyce, CW, Danziger, A, Fawaz, MV, Kelly, M, Murgolo, N, Robbins, JA, Vavrek, M, Zhao, L, Lei, Z, Guo, Z, Reaksudsan, K, Steel, RWJ, Hodder, AN, Ngo, A, Dziekan, JM, Thompson, JK, Triglia, T, Birkinshaw, RW, Penington, JS, Scally, SW, Dans, MG, Coyle, R, Sevilleno, N, Orban, A, Feufack-Donfack, LB, Popovici, J, Lee, MCS, Papenfuss, A, Lowes, KN, Sleebs, BE, McCarthy, JS, McCauley, JA, Boddey, JA, Olsen, DB & Cowman, AF 2026, 'MK-7602: a potent multi-stage dual-targeting antimalarial', EBioMedicine, vol. 123, 106061. https://doi.org/10.1016/j.ebiom.2025.106061

TY - JOUR

T1 - MK-7602

T2 - a potent multi-stage dual-targeting antimalarial

AU - Favuzza, Paola

AU - Palandri, Josephine

AU - de Lera Ruiz, Manuel

AU - Bailey, Wendy

AU - Boyce, Christopher W.

AU - Danziger, Andrew

AU - Fawaz, Maria V.

AU - Kelly, Michael

AU - Murgolo, Nicholas

AU - Robbins, Jonathan A.

AU - Vavrek, Marissa

AU - Zhao, Lianyun

AU - Lei, Zhiyu

AU - Guo, Zhuyan

AU - Reaksudsan, Kitsanapong

AU - Steel, Ryan W. J.

AU - Hodder, Anthony N.

AU - Ngo, Anna

AU - Dziekan, Jerzy M.

AU - Thompson, Jennifer K.

AU - Triglia, Tony

AU - Birkinshaw, Richard W.

AU - Penington, Jocelyn Sietsma

AU - Scally, Stephen W.

AU - Dans, Madeline G.

AU - Coyle, Rachael

AU - Sevilleno, Nicole

AU - Orban, Agnes

AU - Feufack-Donfack, Lionel Brice

AU - Popovici, Jean

AU - Lee, Marcus C. S.

AU - Papenfuss, Anthony

AU - Lowes, Kym N.

AU - Sleebs, Brad E.

AU - McCarthy, James S.

AU - McCauley, John A.

AU - Boddey, Justin A.

AU - Olsen, David B.

AU - Cowman, Alan F.

PY - 2026/1

Y1 - 2026/1

N2 - Background: The global burden of malaria remains substantial, and increasing parasite resistance to current antimalarials necessitates the development of drugs with unique mechanisms of action. This study aimed to develop and characterise a new antimalarial compound targeting Plasmodium aspartic proteases.Methods: We conducted high-throughput screening, medicinal chemistry optimisation, and extensive in vitro and in vivo testing to develop and evaluate MK-7602, a dual inhibitor of plasmepsins IX and X.Findings: MK-7602, a clinical candidate, acts as a dual sub-nanomolar inhibitor of plasmepsins IX and X in multiple Plasmodium species. It exhibits favourable pharmacokinetic properties and a promising safety profile. MK-7602 demonstrates activity against liver and blood life-cycle stages of the parasite and blocks transmission to mosquitoes. Importantly, it shows a high barrier to resistance development and lacks cross-resistance with Plasmodium falciparum strains resistant to other antimalarials. MK-7602 effectively inhibits both wild-type parasites and those with increased plasmepsin expression, highlighting its potential to overcome existing resistance mechanisms.Interpretation: MK-7602 represents a new class of antimalarial for treating uncomplicated malaria with a new mechanism of action and the potential to address drug-resistant malaria. Clinical evaluation of MK-7602's activity against P. falciparum is ongoing.

AB - Background: The global burden of malaria remains substantial, and increasing parasite resistance to current antimalarials necessitates the development of drugs with unique mechanisms of action. This study aimed to develop and characterise a new antimalarial compound targeting Plasmodium aspartic proteases.Methods: We conducted high-throughput screening, medicinal chemistry optimisation, and extensive in vitro and in vivo testing to develop and evaluate MK-7602, a dual inhibitor of plasmepsins IX and X.Findings: MK-7602, a clinical candidate, acts as a dual sub-nanomolar inhibitor of plasmepsins IX and X in multiple Plasmodium species. It exhibits favourable pharmacokinetic properties and a promising safety profile. MK-7602 demonstrates activity against liver and blood life-cycle stages of the parasite and blocks transmission to mosquitoes. Importantly, it shows a high barrier to resistance development and lacks cross-resistance with Plasmodium falciparum strains resistant to other antimalarials. MK-7602 effectively inhibits both wild-type parasites and those with increased plasmepsin expression, highlighting its potential to overcome existing resistance mechanisms.Interpretation: MK-7602 represents a new class of antimalarial for treating uncomplicated malaria with a new mechanism of action and the potential to address drug-resistant malaria. Clinical evaluation of MK-7602's activity against P. falciparum is ongoing.

KW - Antimalarial drug

KW - Aspartic proteases

KW - Falciparum

KW - Malaria

KW - Plasmepsin

KW - Vivax

UR - https://www.scopus.com/pages/publications/105025226197

U2 - 10.1016/j.ebiom.2025.106061

DO - 10.1016/j.ebiom.2025.106061

M3 - Article

C2 - 41353980

AN - SCOPUS:105025226197

SN - 2352-3964

VL - 123

JO - EBioMedicine

JF - EBioMedicine

M1 - 106061

ER -

MK-7602: a potent multi-stage dual-targeting antimalarial

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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