Diversity-oriented natural product platform identifies plant constituents targeting Plasmodium falciparum

Malaria Journal

Research

Julie Clark¹  Anang A. Shelat¹  Michele Connelly¹  Nathaniel Twarog¹  John J. Bowling¹  Ying Tu¹  Cynthia Jeffries¹  R. Kiplin Guy¹  David Smithson²  Shabana I. Khan³  Ilias Muhammad³  Mei Wang³  John P. Hester³  Jin Zhang³  Mohamed A. Ibrahim³  Melissa R. Jacob³  Mohamed A. Zaki⁴  Babu L. Tekwani⁵  Larry A. Walker⁵  Vladimir Samoylenko⁶ 

[1] Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, 38105, Memphis, TN, USA;Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, 38105, Memphis, TN, USA;Genentech, San Francisco, CA, USA;National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi, 38677, University, MS, USA;National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi, 38677, University, MS, USA;Beni-Suef University, Beni-Suef, Egypt;National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi, 38677, University, MS, USA;Department of Biomolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi, 38677, University, MS, USA;National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi, 38677, University, MS, USA;Keiser University, West Palm Beach, FL, USA;

关键词: Drug discovery;    Spectrometry;    Natural products;    Alkaloids;    Terpenes;    Antimalarial;    Plasmodium;    UPLC-ELSD-PDA-ESI–MS;    Berberis thunbergii;    Eugenia rigida;   

DOI  :  10.1186/s12936-016-1313-7

 received in 2016-03-04, accepted in 2016-04-27,  发布年份 2016

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© Zhang et al. 2016