Brodie L. Bailey

University of Melbourne

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Alan F. Cowman

Walter and Eliza Hall Institute of Medical Research

Brad E. Sleebs

Walter and Eliza Hall Institute of Medical Research

Paola Favuzza

Swiss Tropical and Public Health Institute

Anna Ngo

Ruhr University Bochum

Kym N. Lowes

Walter and Eliza Hall Institute of Medical Research

Richard W. Birkinshaw

University of Melbourne

David B. Olsen

United States Military Academy

Manuel de Lera Ruiz

United States Military Academy

Nicholas Murgolo

Merck & Co., Inc., Rahway, NJ, USA (United States)

S.W. Scally

University of Melbourne

Cooperative Institutions

Walter and Eliza Hall Institute of Medical Research

University of Melbourne

Merck & Co., Inc., Rahway, NJ, USA (United States)

GTx (United States)

Monash University

United States Military Academy

The Royal Melbourne Hospital

Australian National University

University of Adelaide

Harvard University

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Optimisation of 2-(N-phenyl carboxamide) triazolopyrimidine antimalarials with moderate to slow acting erythrocytic stage activity

Bioorganic Chemistry (2021)

Brodie L. Bailey William Nguyen Anna Ngo C.D. Goodman Maria R. Gancheva

Carboxamide

Phenotypic screening

ADME

10.1016/j.bioorg.2021.105244

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Citations (16)

7-N-Substituted-3-oxadiazole Quinolones with Potent Antimalarial Activity Target the Cytochrome bc₁ Complex

ACS Infectious Diseases (2023)

William Nguyen Madeline G. Dans Iain Currie Jon Kyle Awalt Brodie L. Bailey

The development of new antimalarials is required because of the threat of resistance to current antimalarial therapies. To discover new antimalarial chemotypes, we screened the Janssen Jumpstarter library against the P. falciparum asexual parasite and identified the 7-N-substituted-3-oxadiazole quinolone hit class. We established the structure–activity relationship and optimized the antimalarial potency. The optimized analog WJM228 (17) showed robust metabolic stability in vitro, although the aqueous solubility was limited. Forward genetic resistance studies uncovered that WJM228 targets the Qo site of cytochrome b (cyt b), an important component of the mitochondrial electron transport chain (ETC) that is essential for pyrimidine biosynthesis and an established antimalarial target. Profiling against drug-resistant parasites confirmed that WJM228 confers resistance to the Qo site but not Qi site mutations, and in a biosensor assay, it was shown to impact the ETC via inhibition of cyt b. Consistent with other cyt b targeted antimalarials, WJM228 prevented pre-erythrocytic parasite and male gamete development and reduced asexual parasitemia in a P. berghei mouse model of malaria. Correcting the limited aqueous solubility and the high susceptibility to cyt b Qo site resistant parasites found in the clinic will be major obstacles in the future development of the 3-oxadiazole quinolone antimalarial class.

Plasmodium berghei

Oxadiazole

10.1021/acsinfecdis.2c00607

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Citations (13)

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

Structure (2022)

Anthony N. Hodder Janni Christensen S.W. Scally Tony Triglia Anna Ngo

10.1016/j.str.2022.03.018

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Citations (15)

Chemo‐proteomics in antimalarial target identification and engagement

Medicinal Research Reviews (2023)

Brodie L. Bailey William Nguyen Alan F. Cowman Brad E. Sleebs

Abstract Humans have lived in tenuous battle with malaria over millennia. Today, while much of the world is free of the disease, areas of South America, Asia, and Africa still wage this war with substantial impacts on their social and economic development. The threat of widespread resistance to all currently available antimalarial therapies continues to raise concern. Therefore, it is imperative that novel antimalarial chemotypes be developed to populate the pipeline going forward. Phenotypic screening has been responsible for the majority of the new chemotypes emerging in the past few decades. However, this can result in limited information on the molecular target of these compounds which may serve as an unknown variable complicating their progression into clinical development. Target identification and validation is a process that incorporates techniques from a range of different disciplines. Chemical biology and more specifically chemo‐proteomics have been heavily utilized for this purpose. This review provides an in‐depth summary of the application of chemo‐proteomics in antimalarial development. Here we focus particularly on the methodology, practicalities, merits, and limitations of designing these experiments. Together this provides learnings on the future use of chemo‐proteomics in antimalarial development.

Identification

Drug Development

Proteogenomics

10.1002/med.21975

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Citations (18)

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

Research Square (Research Square) (2021)

Alan F. Cowman Anthony N. Hodder Janni Christensen S.W. Scally Tony Triglia

Abstract Plasmepsin IX (PMIX) and X (PMX) are aspartyl proteases of Plasmodium spp. that play essential roles in parasite egress, invasion and development. Consequently, they are important drug targets for Plasmodium falciparum and P. vivax. WM4 and WM382 are potent inhibitors of PMIX and PMX that block invasion of liver and blood stages and transmission to mosquitoes. WM4 specifically inhibits PMX whilst WM382 is a dual inhibitor of PMIX and PMX. To understand the function of PMIX and PMX proteases we identified new protein substrates in P. falciparum and together with detailed kinetic analyses and structural analyses identified key molecular interactions in the active site responsible for the specificity of WM4 and WM382 inhibition. The crystal structures of PMX apo enzyme and the protease/drug complexes of PMX/WM382 and PMX/WM4 for P. falciparum and P. vivax have been solved. We show PMIX and PMX have similar substrate selectivity, however, there are distinct differences for both peptide and full-length protein substrates through differences in localised 3-dimensional structures for the enzyme substrate-binding cleft and substrate interface. The differences in affinities of WM4 and WM382 binding for PMIX and PMX map to variations in surface interactions with each protease in the S' region of the active sites. Crystal structures of PMX reveal interactions and mechanistic detail on the selectivity of drug binding which will be important for further development of clinical candidates against these important molecular targets.

10.21203/rs.3.rs-944781/v2

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Citations (0)

Basis for Drug Selectivity of Plasmepsin IX and X Inhibition for <i>Plasmodium falciparum</i> and <i>vivax</i>

SSRN Electronic Journal (2021)

Anthony N. Hodder Janni Christensen S.W. Scally Tony Triglia Anna Ngo

Plasmepsin IX (PMIX) and X (PMX) are aspartyl proteases of Plasmodium spp. that play essential roles in parasite egress, invasion and development. Consequently, they are important drug targets for Plasmodium falciparum and P. vivax. WM4 and WM382 are potent inhibitors of PMIX and PMX that block invasion of liver and blood stages and transmission to mosquitoes. WM4 specifically inhibits PMX whilst WM382 is a dual inhibitor of PMIX and PMX. To understand the function of PMIX and PMX proteases we identified new protein substrates in P. falciparum and together with detailed kinetic analyses and structural analyses identified key molecular interactions in the active site responsible for the specificity of WM4 and WM382 inhibition. The crystal structures of PMX apo enzyme and the protease/drug complexes of PMX/WM382 and PMX/WM4 for P. falciparum and P. vivax have been solved. We show PMIX and PMX have similar substrate selectivity, however, there are distinct differences for both peptide and full-length protein substrates through differences in localised 3-dimensional structures for the enzyme substrate-binding cleft and substrate interface. The differences in affinities of WM4 and WM382 binding for PMIX and PMX map to variations in surface interactions with each protease in the S' region of the active sites. Crystal structures of PMX reveal interactions and mechanistic detail on the selectivity of drug binding which will be important for further development of clinical candidates against these important molecular targets.

10.2139/ssrn.3948205

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Citations (1)

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

Research Square (Research Square) (2021)

Anthony N. Hodder S.W. Scally Tony Triglia Anna Ngo Richard W. Birkinshaw

10.21203/rs.3.rs-944781/v1

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Citations (0)