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Diversity-oriented synthesis yields novel multistage antimalarial inhibitors
Nobutaka Kato1, Eamon Comer1, Tomoyo Sakata-Kato2
1Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Nature
|September 8, 2016
Summary
Researchers discovered novel bicyclic azetidines that cure malaria in mice with a single dose. These compounds target phenylalanyl-tRNA synthetase, offering potential for new antimalarial drugs and transmission prevention.
Area of Science:
- Medicinal Chemistry
- Parasitology
- Drug Discovery
Background:
- Antimalarial drug discovery traditionally relies on natural products and synthetic compounds.
- There is a need for novel antimalarial agents with new mechanisms of action to combat resistance.
- Screening collections often lack diverse chemical scaffolds, potentially missing new therapeutic leads.
Purpose of the Study:
- To explore a diverse collection of synthetic compounds with natural product-like 3D features for novel antimalarial activity.
- To identify compounds with new mechanisms of action against malaria parasites.
- To evaluate the therapeutic potential of identified compounds in preclinical models.
Main Methods:
- Utilized a diverse library of synthetic compounds with natural product-like three-dimensional features.
- Screened compounds for antimalarial activity.
- Identified bicyclic azetidines as a promising class of compounds.
- Investigated the mechanism of action, including target identification (phenylalanyl-tRNA synthetase).
- Assessed in vivo efficacy in mouse models for curative and preventative potential.
Main Results:
- Identified novel antimalarial compounds, including bicyclic azetidines, with diverse mechanisms of action.
- Discovered that bicyclic azetidines inhibit phenylalanyl-tRNA synthetase, a new antimalarial target.
- Demonstrated that these bicyclic azetidines are curative in mice at a single, low dose.
- Showed activity against all parasite life stages in multiple in vivo efficacy models.
Conclusions:
- Bicyclic azetidines represent a promising new class of antimalarial agents.
- Inhibition of phenylalanyl-tRNA synthetase is a viable new target for antimalarial drug development.
- These compounds have the potential to cure, prevent malaria transmission, and protect at-risk populations with a single oral dose.
- Diversity-oriented synthesis is a powerful strategy for discovering novel therapeutics and targets.
