title: Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions.
abstract: Malaria remains a global health problem, and though international efforts for treatment and eradication have made some headway, the emergence of drug-resistant parasites threatens this progress. Antimalarial therapeutics acting via novel mechanisms are urgently required. Plasmodium falciparum M1 and M17 are neutral aminopeptidases which are essential for parasite growth and development. Previous work in our group has identified inhibitors capable of dual inhibition of PfA-M1 and PfA-M17, and revealed further regions within the protease S1 pockets that could be exploited in the development of ligands with improved inhibitory activity. Herein, we report the structure-based design and synthesis of novel hydroxamic acid analogues that are capable of potent inhibition of both PfA-M1 and PfA-M17. Furthermore, the developed compounds potently inhibit Pf growth in culture, including the multi-drug resistant strain Dd2. The ongoing development of dual PfA-M1/PfA-M17 inhibitors continues to be an attractive strategy for the design of novel antimalarial therapeutics.
authors.affiliation: Biomedicine Discovery Institute and Department of Microbiology, Melbourne, VIC 3800, Australia; Department of Biochemistry and Molecular Biology Monash University (Clayton Campus), Melbourne, VIC 3800, Australia.
authors.forename: Nyssa
authors.initials: N
authors.lastname: Drinkwater
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, VIC 3052, Australia.
authors.forename: Natalie B
authors.initials: NB
authors.lastname: Vinh
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, VIC 3052, Australia.
authors.forename: Shailesh N
authors.initials: SN
authors.lastname: Mistry
authors.affiliation: Biomedicine Discovery Institute and Department of Microbiology, Melbourne, VIC 3800, Australia; Department of Biochemistry and Molecular Biology Monash University (Clayton Campus), Melbourne, VIC 3800, Australia.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Bamert
authors.affiliation: Dipartmento di Biologia e Biotecnologie "Charles Darwin", Sapienza Universita di Roma, 00185 Roma, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Ruggeri
authors.affiliation: Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia.
authors.forename: John P
authors.initials: JP
authors.lastname: Holleran
authors.affiliation: Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia.
authors.forename: Sasdekumar
authors.initials: S
authors.lastname: Loganathan
authors.affiliation: Dipartimento di Scienze Biochimiche "A. Rossi Fanelli", Sapienza Università di Roma, 00185 Roma, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Paiardini
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, VIC 3052, Australia.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, VIC 3052, Australia.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Powell
authors.affiliation: Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia.
authors.forename: Vicky M
authors.initials: VM
authors.lastname: Avery
authors.affiliation: Biomedicine Discovery Institute and Department of Microbiology, Melbourne, VIC 3800, Australia; Department of Biochemistry and Molecular Biology Monash University (Clayton Campus), Melbourne, VIC 3800, Australia. Electronic address: Sheena.McGowan@monash.edu.
authors.forename: Sheena
authors.initials: S
authors.lastname: McGowan
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, VIC 3052, Australia. Electronic address: Peter.Scammells@monash.edu.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scammells
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology*; D016778:Malaria, Falciparum / Q000188:drug therapy; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000187:drug effects*; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D015032:Zinc / Q000378:metabolism
chemical_list: D000962:Antimalarials; D006877:Hydroxamic Acids; D011480:Protease Inhibitors; D015800:Protozoan Proteins; D000626:Aminopeptidases; D015032:Zinc
keywords: Aminopeptidase inhibitors; Hydroxamic acid; Malaria; Plasmodium falciparum; Zinc-binding group