Natural Products-Based Lead Discovery by HPLC Activity Profiling

The future of natural product-based drug discovery critically depends on efficient and targeted approaches for early compound identification and dereplication. For that purpose we have established a technology platform combining pre-formatted extract libraries with a miniaturized and highly effective approach termed HPLC-based activity profiling. The flexibility of our platform enables discovery projects to be conducted in decentralized collaborative settings.

In a collaboration with pharmacologists at the University of Vienna we have been screening for GABA_A receptor modulatory properties in an extract library of traditional medicinal plants. We identified a spectrum of compounds with scaffolds that are new for the target. Selected compounds and their in vitro and in vivo pharmacological characterization will be presented. The development of the GABA_A receptor modulator piperine into a non-TRPV1 activating lead SCT-66 will be highlighted.

Neglected infectious diseases constitute a major health problem affecting over 800 million people worldwide. Natural products such as quinine and artemisinine have been essential for the development of effective anti-protozoan treatments. In a collaboration with the Swiss Tropical and Public Health Institute we have been pursuing natural product based lead discovery against protozoan diseases. HPLC-based activity profiling led to identification of numerous active molecules belonging to different compound classes. The discovery of cynaropicrin as the first plant metabolite with in vivo activity in the T. brucei rhodesiense STIB 900 acute mouse model will be highlighted, and results from mechanistic studies with the compound will be discussed.