A Phenotarget Approach for Identifying an Alkaloid Interacting with the Tuberculosis Protein Rv1466

A Phenotarget Approach for Identifying an Alkaloid Interacting with the Tuberculosis Protein Rv1466

In recent years, there has been a revival of interest in phenotypic-based drug discovery (PDD) due to target-based drug discovery (TDD) falling below expectations. Both PDD and TDD have their unique advantages and should be used as complementary methods in drug discovery. The PhenoTarget approach co...

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Main Authors: Yan Xie, Yunjiang Feng, Angela Di Capua, Tin Mak, Garry W. Buchko, Peter J. Myler, Miaomiao Liu, Ronald J. Quinn
Format: Article
Language:English
Published: MDPI AG 2020-03-01
Series:Marine Drugs
Subjects:
phenotarget approach
mrms
protein-ligand complex
polycarpine
Online Access:https://www.mdpi.com/1660-3397/18/3/149
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spelling doaj-3d0b864a9b864d6cab316ffff869ec412020-11-25T02:27:27ZengMDPI AGMarine Drugs1660-33972020-03-0118314910.3390/md18030149md18030149A Phenotarget Approach for Identifying an Alkaloid Interacting with the Tuberculosis Protein Rv1466Yan Xie0Yunjiang Feng1Angela Di Capua2Tin Mak3Garry W. Buchko4Peter J. Myler5Miaomiao Liu6Ronald J. Quinn7Griffith Institute for Drug Discovery, Griffith University, Brisbane, Queensland 4111, AustraliaGriffith Institute for Drug Discovery, Griffith University, Brisbane, Queensland 4111, AustraliaGriffith Institute for Drug Discovery, Griffith University, Brisbane, Queensland 4111, AustraliaGriffith Institute for Drug Discovery, Griffith University, Brisbane, Queensland 4111, AustraliaEarth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, WA 99354, USACenter for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WA 98109-5219, USAGriffith Institute for Drug Discovery, Griffith University, Brisbane, Queensland 4111, AustraliaGriffith Institute for Drug Discovery, Griffith University, Brisbane, Queensland 4111, AustraliaIn recent years, there has been a revival of interest in phenotypic-based drug discovery (PDD) due to target-based drug discovery (TDD) falling below expectations. Both PDD and TDD have their unique advantages and should be used as complementary methods in drug discovery. The PhenoTarget approach combines the strengths of the PDD and TDD approaches. Phenotypic screening is conducted initially to detect cellular active components and the hits are then screened against a panel of putative targets. This PhenoTarget protocol can be equally applied to pure compound libraries as well as natural product fractions. Here we described the use of the PhenoTarget approach to identify an anti-tuberculosis lead compound. Fractions from <i>Polycarpa aurata</i> were identified with activity against <i>Mycobacterium tuberculosis</i> H37Rv. Native magnetic resonance mass spectrometry (MRMS) against a panel of 37 proteins from <i>Mycobacterium</i> proteomes showed that a fraction from a 95% ethanol re-extraction specifically formed a protein-ligand complex with Rv1466, a putative uncharacterized <i>Mycobacterium tuberculosis</i> protein. The natural product responsible was isolated and characterized to be polycarpine. The molecular weight of the ligand bound to Rv1466, 233 Da, was half the molecular weight of polycarpine less one proton, indicating that polycarpine formed a covalent bond with Rv1466.https://www.mdpi.com/1660-3397/18/3/149phenotarget approachmrmsprotein-ligand complexpolycarpine
collection DOAJ
language English
format Article
sources DOAJ
author Yan Xie
Yunjiang Feng
Angela Di Capua
Tin Mak
Garry W. Buchko
Peter J. Myler
Miaomiao Liu
Ronald J. Quinn
spellingShingle Yan Xie
Yunjiang Feng
Angela Di Capua
Tin Mak
Garry W. Buchko
Peter J. Myler
Miaomiao Liu
Ronald J. Quinn
A Phenotarget Approach for Identifying an Alkaloid Interacting with the Tuberculosis Protein Rv1466
Marine Drugs
phenotarget approach
mrms
protein-ligand complex
polycarpine
author_facet Yan Xie
Yunjiang Feng
Angela Di Capua
Tin Mak
Garry W. Buchko
Peter J. Myler
Miaomiao Liu
Ronald J. Quinn
author_sort Yan Xie
title A Phenotarget Approach for Identifying an Alkaloid Interacting with the Tuberculosis Protein Rv1466
title_short A Phenotarget Approach for Identifying an Alkaloid Interacting with the Tuberculosis Protein Rv1466
title_full A Phenotarget Approach for Identifying an Alkaloid Interacting with the Tuberculosis Protein Rv1466
title_fullStr A Phenotarget Approach for Identifying an Alkaloid Interacting with the Tuberculosis Protein Rv1466
title_full_unstemmed A Phenotarget Approach for Identifying an Alkaloid Interacting with the Tuberculosis Protein Rv1466
title_sort phenotarget approach for identifying an alkaloid interacting with the tuberculosis protein rv1466
publisher MDPI AG
series Marine Drugs
issn 1660-3397
publishDate 2020-03-01
description In recent years, there has been a revival of interest in phenotypic-based drug discovery (PDD) due to target-based drug discovery (TDD) falling below expectations. Both PDD and TDD have their unique advantages and should be used as complementary methods in drug discovery. The PhenoTarget approach combines the strengths of the PDD and TDD approaches. Phenotypic screening is conducted initially to detect cellular active components and the hits are then screened against a panel of putative targets. This PhenoTarget protocol can be equally applied to pure compound libraries as well as natural product fractions. Here we described the use of the PhenoTarget approach to identify an anti-tuberculosis lead compound. Fractions from <i>Polycarpa aurata</i> were identified with activity against <i>Mycobacterium tuberculosis</i> H37Rv. Native magnetic resonance mass spectrometry (MRMS) against a panel of 37 proteins from <i>Mycobacterium</i> proteomes showed that a fraction from a 95% ethanol re-extraction specifically formed a protein-ligand complex with Rv1466, a putative uncharacterized <i>Mycobacterium tuberculosis</i> protein. The natural product responsible was isolated and characterized to be polycarpine. The molecular weight of the ligand bound to Rv1466, 233 Da, was half the molecular weight of polycarpine less one proton, indicating that polycarpine formed a covalent bond with Rv1466.
topic phenotarget approach
mrms
protein-ligand complex
polycarpine
url https://www.mdpi.com/1660-3397/18/3/149
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