Abstract
BackgroundA diverse library of pre-fractionated plant extracts, generated by an automated high-throughput system, was tested using an in vitro anti-malarial screening platform to identify known or new natural products for lead development. The platform identifies hits on the basis of in vitro growth inhibition of Plasmodium falciparum and counter-screens for cytotoxicity to human foreskin fibroblast or embryonic kidney cell lines. The physical library was supplemented by early-stage collection of analytical data for each fraction to aid rapid identification of the active components within each screening hit.ResultsA total of 16,177 fractions from 1300 plants were screened, identifying several P. falciparum inhibitory fractions from 35 plants. Although individual fractions were screened for bioactivity to ensure adequate signal in the analytical characterizations, fractions containing less than 2.0 mg of dry weight were combined to produce combined fractions (COMBIs). Fractions of active COMBIs had EC50 values of 0.21–50.28 and 0.08–20.04 µg/mL against chloroquine-sensitive and -resistant strains, respectively. In Berberis thunbergii, eight known alkaloids were dereplicated quickly from its COMBIs, but berberine was the most-active constituent against P. falciparum. The triterpenoids α-betulinic acid and β-betulinic acid of Eugenia rigida were also isolated as hits. Validation of the anti-malarial discovery platform was confirmed by these scaled isolations from B. thunbergii and E. rigida.ConclusionsThese results demonstrate the value of curating and exploring a library of natural products for small molecule drug discovery. Attention given to the diversity of plant species represented in the library, focus on practical analytical data collection, and the use of counter-screens all facilitate the identification of anti-malarial compounds for lead development or new tools for chemical biology.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-016-1313-7) contains supplementary material, which is available to authorized users.
Highlights
A diverse library of pre-fractionated plant extracts, generated by an automated high-throughput system, was tested using an in vitro anti-malarial screening platform to identify known or new natural products for lead development
High-throughput screening against chloroquine (CQ)sensitive (3D7) and -resistant (K1) strains of P. falciparum was performed to demonstrate the utility of the plant natural product (NP) library generated by automated high-throughput systems (AHTS) fractionation
Species considered endangered or threatened for extinction accounted for 123 of the 900 fraction hits—accounting for more than 13 % of all hits having greater than 50 % inhibition in either P. falciparum strain tested—reinforcing the need to conserve these resources globally
Summary
A diverse library of pre-fractionated plant extracts, generated by an automated high-throughput system, was tested using an in vitro anti-malarial screening platform to identify known or new natural products for lead development. Plants provide prototype molecules and novel templates for drug development, especially for the treatment of malaria [1]. St Laurent et al reported that artemisinin-resistant Plasmodium falciparum parasites are rapidly spreading in Southeast Asia [5], necessitating a steady pipeline of novel anti-malarial agents [6]. This project focused resources on screening NPs for new leads that target the malaria parasite
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
