Currently Available Strategies for Target Identification of Bioactive Natural Products

Overview

Journal Front Chem

Specialty Chemistry

Date 2021 Oct 18

PMID 34660543

Citations 10

Authors

Gen Li

Xuling Peng

Yajing Guo

Shaoxuan Gong

Shijie Cao

Feng Qiu

Affiliations

Soon will be listed here.

Abstract

In recent years, biologically active natural products have gradually become important agents in the field of drug research and development because of their wide availability and variety. However, the target sites of many natural products are yet to be identified, which is a setback in the pharmaceutical industry and has seriously hindered the translation of research findings of these natural products as viable candidates for new drug exploitation. This review systematically describes the commonly used strategies for target identification via the application of probe and non-probe approaches. The merits and demerits of each method were summarized using recent examples, with the goal of comparing currently available methods and selecting the optimum techniques for identifying the targets of bioactive natural products.

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References

Zhao W, Cross A, Crowe-McAuliffe C, Weigert-Munoz A, Csatary E, Solinski A . The Natural Product Elegaphenone Potentiates Antibiotic Effects against Pseudomonas aeruginosa. Angew Chem Int Ed Engl. 2019; 58(25):8581-8584. PMC: 6555641. DOI: 10.1002/anie.201903472. View

Morretta E, Esposito R, Festa C, Riccio R, Casapullo A, Monti M . Discovering the Biological Target of 5-epi-Sinuleptolide Using a Combination of Proteomic Approaches. Mar Drugs. 2017; 15(10). PMC: 5666420. DOI: 10.3390/md15100312. View

Yue Q, Feng L, Cao B, Liu M, Zhang D, Wu W . Proteomic Analysis Revealed the Important Role of Vimentin in Human Cervical Carcinoma HeLa Cells Treated With Gambogic Acid. Mol Cell Proteomics. 2015; 15(1):26-44. PMC: 4762520. DOI: 10.1074/mcp.M115.053272. View

Margarucci L, Monti M, Cassiano C, Mozzicafreddo M, Angeletti M, Riccio R . Chemical proteomics-driven discovery of oleocanthal as an Hsp90 inhibitor. Chem Commun (Camb). 2013; 49(52):5844-6. DOI: 10.1039/c3cc41858h. View

Zhao Q, Ding Y, Deng Z, Lee O, Gao P, Chen P . Natural products triptolide, celastrol, and withaferin A inhibit the chaperone activity of peroxiredoxin I. Chem Sci. 2017; 6(7):4124-4130. PMC: 5497274. DOI: 10.1039/c5sc00633c. View

Kreuzer J, Bach N, Forler D, Sieber S . Target discovery of acivicin in cancer cells elucidates its mechanism of growth inhibition†Electronic supplementary information (ESI) available: Synthesis, cloning, protein expression, purification and biochemical assays. See DOI:.... Chem Sci. 2015; 6(1):237-245. PMC: 4285139. DOI: 10.1039/c4sc02339k. View

Yue Q, Xie F, Guan S, Ma C, Yang M, Jiang B . Interaction of Ganoderma triterpenes with doxorubicin and proteomic characterization of the possible molecular targets of Ganoderma triterpenes. Cancer Sci. 2008; 99(7):1461-70. PMC: 11159042. DOI: 10.1111/j.1349-7006.2008.00824.x. View

Lyu J, Ruan C, Zhang X, Wang Y, Li K, Ye M . Microparticle-Assisted Precipitation Screening Method for Robust Drug Target Identification. Anal Chem. 2020; 92(20):13912-13921. DOI: 10.1021/acs.analchem.0c02756. View

Maurais A, Weerapana E . Reactive-cysteine profiling for drug discovery. Curr Opin Chem Biol. 2019; 50:29-36. PMC: 6584045. DOI: 10.1016/j.cbpa.2019.02.010. View

10.

Guo J, Gu X, Zheng M, Zhang Y, Chen L, Li H . Azacoccone E inhibits cancer cell growth by targeting 3-phosphoglycerate dehydrogenase. Bioorg Chem. 2019; 87:16-22. DOI: 10.1016/j.bioorg.2019.02.037. View

11.

Wang X, Huang S, Heston W, Guo H, Wang B, Basilion J . Development of targeted near-infrared imaging agents for prostate cancer. Mol Cancer Ther. 2014; 13(11):2595-606. PMC: 4472004. DOI: 10.1158/1535-7163.MCT-14-0422. View

12.

Vetterli S, Zerbe K, Muller M, Urfer M, Mondal M, Wang S . Thanatin targets the intermembrane protein complex required for lipopolysaccharide transport in . Sci Adv. 2018; 4(11):eaau2634. PMC: 6235536. DOI: 10.1126/sciadv.aau2634. View

13.

Lomenick B, Olsen R, Huang J . Identification of direct protein targets of small molecules. ACS Chem Biol. 2010; 6(1):34-46. PMC: 3031183. DOI: 10.1021/cb100294v. View

14.

Wang L, Liao L, Lv H, Liu D, Dong W, Zhu J . Highly Selective Activation of Heat Shock Protein 70 by Allosteric Regulation Provides an Insight into Efficient Neuroinflammation Inhibition. EBioMedicine. 2017; 23:160-172. PMC: 5605382. DOI: 10.1016/j.ebiom.2017.08.011. View

15.

Newman D, Cragg G . Natural Products as Sources of New Drugs from 1981 to 2014. J Nat Prod. 2016; 79(3):629-61. DOI: 10.1021/acs.jnatprod.5b01055. View

16.

Battenberg O, Yang Y, Verhelst S, Sieber S . Target profiling of 4-hydroxyderricin in S. aureus reveals seryl-tRNA synthetase binding and inhibition by covalent modification. Mol Biosyst. 2013; 9(3):343-51. DOI: 10.1039/c2mb25446h. View

17.

Brodziak-Jarosz L, Fujikawa Y, Pastor-Flores D, Kasikci S, Jirasek P, Pitzl S . A click chemistry approach identifies target proteins of xanthohumol. Mol Nutr Food Res. 2016; 60(4):737-48. DOI: 10.1002/mnfr.201500613. View

18.

Peon A, Naulaerts S, Ballester P . Predicting the Reliability of Drug-target Interaction Predictions with Maximum Coverage of Target Space. Sci Rep. 2017; 7(1):3820. PMC: 5476590. DOI: 10.1038/s41598-017-04264-w. View

19.

Zhao B, Liu N, Chen L, Geng S, Fan Z, Xing J . Direct label-free methods for identification of target proteins in agrochemicals. Int J Biol Macromol. 2020; 164:1475-1483. DOI: 10.1016/j.ijbiomac.2020.07.237. View

20.

Quek N, Matthews J, Bloor S, Jones D, Bircham P, Heathcott R . The novel equisetin-like compound, TA-289, causes aberrant mitochondrial morphology which is independent of the production of reactive oxygen species in Saccharomyces cerevisiae. Mol Biosyst. 2013; 9(8):2125-33. DOI: 10.1039/c3mb70056a. View