Primary Citation of Related Structures: 9Y65, 9YC0, 9YC7
PubMed Abstract:
Malaria remains a global health burden and the emergence of parasite-resistance to frontline drugs highlights an urgent need for new therapeutics with novel mechanisms of action. Inhibiting aminopeptidases, in particular the Plasmodium falciparum M1 and M17 aminopeptidases ( Pf A-M1 and Pf A-M17 respectively) has been shown to cause parasite death. In this study, both ligand-based and structure-based design strategies were utilized to identify novel scaffolds that act as dual inhibitors of these enzymes. Structural studies supported the improved activity showing strong hydrophobic and additional hydrogen interactions between the new cores and the S1 pocket of the enzymes. These inhibitors were highly effective against Plasmodium vivax and Plasmodium berghei , showing cross-peptidase and cross-species activity while also retaining activity against multidrug resistant P. falciparum strains. Progression to in vivo efficacy studies showed reduction in parasitaemia in mice infected with P. berghei demonstrating encouraging prospects to develop suitable drug-like candidates for the treatment of malaria.
Organizational Affiliation:
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
School of Medicine, Deakin University, Geelong, Victoria 3216, Australia.
The Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, Victoria 3216, Australia.
New Medicines and Diagnostics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Victoria 3800, Australia.
BB [auth C] CB [auth C] EF [auth J] FC [auth E] FF [auth J]
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AE [auth H], AF [auth J], BC [auth D], DB [auth C], GF [auth J], IA [auth B], JA [auth B], KD [auth G], LE [auth I], MA [auth B], QG [auth L], VA [auth C], WA [auth C]
DIMETHYL SULFOXIDE C2 H6 O S IAZDPXIOMUYVGZ-UHFFFAOYSA-N
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