Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Molecular Pharmacology
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Molecular Pharmacology

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Visit molpharm on Facebook
  • Follow molpharm on Twitter
  • Follow molpharm on LinkedIn
Research ArticleArticle

Physiologic Targets and Modes of Action for CBL0137, a Lead for Human African Trypanosomiasis Drug Development

Carlos E. Sanz-Rodríguez, Benjamin Hoffman, Paul J. Guyett, Andrei Purmal, Baljinder Singh, Michael P. Pollastri and Kojo Mensa-Wilmot
Molecular Pharmacology July 2022, 102 (1) 1-16; DOI: https://doi.org/10.1124/molpharm.121.000430
Carlos E. Sanz-Rodríguez
Department of Cellular Biology, University of Georgia, Athens, Georgia (C.E.S.-R., B.H., P.J.G., K.M.-W.); Buffalo Biolabs Inc, Buffalo, New York (A.P.); Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts (B.S., M.P.); and Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, Georgia (K.M.-W.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Benjamin Hoffman
Department of Cellular Biology, University of Georgia, Athens, Georgia (C.E.S.-R., B.H., P.J.G., K.M.-W.); Buffalo Biolabs Inc, Buffalo, New York (A.P.); Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts (B.S., M.P.); and Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, Georgia (K.M.-W.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Paul J. Guyett
Department of Cellular Biology, University of Georgia, Athens, Georgia (C.E.S.-R., B.H., P.J.G., K.M.-W.); Buffalo Biolabs Inc, Buffalo, New York (A.P.); Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts (B.S., M.P.); and Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, Georgia (K.M.-W.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Andrei Purmal
Department of Cellular Biology, University of Georgia, Athens, Georgia (C.E.S.-R., B.H., P.J.G., K.M.-W.); Buffalo Biolabs Inc, Buffalo, New York (A.P.); Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts (B.S., M.P.); and Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, Georgia (K.M.-W.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Baljinder Singh
Department of Cellular Biology, University of Georgia, Athens, Georgia (C.E.S.-R., B.H., P.J.G., K.M.-W.); Buffalo Biolabs Inc, Buffalo, New York (A.P.); Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts (B.S., M.P.); and Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, Georgia (K.M.-W.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michael P. Pollastri
Department of Cellular Biology, University of Georgia, Athens, Georgia (C.E.S.-R., B.H., P.J.G., K.M.-W.); Buffalo Biolabs Inc, Buffalo, New York (A.P.); Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts (B.S., M.P.); and Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, Georgia (K.M.-W.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kojo Mensa-Wilmot
Department of Cellular Biology, University of Georgia, Athens, Georgia (C.E.S.-R., B.H., P.J.G., K.M.-W.); Buffalo Biolabs Inc, Buffalo, New York (A.P.); Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts (B.S., M.P.); and Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, Georgia (K.M.-W.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF
Loading

This article has a correction. Please see:

  • Correction to “Analgesic α-Conotoxin Binding Site on the Human GABAB Receptor” - December 01, 2022

Abstract

CBL0137 is a lead drug for human African trypanosomiasis, caused by Trypanosoma brucei. Herein, we use a four-step strategy to 1) identify physiologic targets and 2) determine modes of molecular action of CBL0137 in the trypanosome. First, we identified fourteen CBL0137-binding proteins using affinity chromatography. Second, we developed hypotheses of molecular modes of action, using predicted functions of CBL0137-binding proteins as guides. Third, we documented effects of CBL0137 on molecular pathways in the trypanosome. Fourth, we identified physiologic targets of the drug by knocking down genes encoding CBL0137-binding proteins and comparing their molecular effects to those obtained when trypanosomes were treated with CBL0137. CBL0137-binding proteins included glycolysis enzymes (aldolase, glyceraldehyde-3-phosphate dehydrogenase, phosphofructokinase, phosphoglycerate kinase) and DNA-binding proteins [universal minicircle sequence binding protein 2, replication protein A1 (RPA1), replication protein A2 (RPA2)]. In chemical biology studies, CBL0137 did not reduce ATP level in the trypanosome, ruling out glycolysis enzymes as crucial targets for the drug. Thus, many CBL0137-binding proteins are not physiologic targets of the drug. CBL0137 inhibited 1) nucleus mitosis, 2) nuclear DNA replication, and 3) polypeptide synthesis as the first carbazole inhibitor of eukaryote translation. RNA interference (RNAi) against RPA1 inhibited both DNA synthesis and mitosis, whereas RPA2 knockdown inhibited mitosis, consistent with both proteins being physiologic targets of CBL0137. Principles used here to distinguish drug-binding proteins from physiologic targets of CBL0137 can be deployed with different drugs in other biologic systems.

SIGNIFICANCE STATEMENT To distinguish drug-binding proteins from physiologic targets in the African trypanosome, we devised and executed a multidisciplinary approach involving biochemical, genetic, cell, and chemical biology experiments. The strategy we employed can be used for drugs in other biological systems.

Footnotes

    • Received October 10, 2021.
    • Accepted April 20, 2022.
  • This work was supported by National Institutes of Health National Institute of Allergy and Infectious Disease [Grant R01-AI126311] and [Grant R01-AI124046] (to K.M.-W.).

  • No author has an actual or perceived conflict of interest with the contents of this article

  • https://doi.org/10.1124/molpharm.121.000430.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics
View Full Text

MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Molecular Pharmacology: 102 (1)
Molecular Pharmacology
Vol. 102, Issue 1
1 Jul 2022
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Molecular Pharmacology article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Physiologic Targets and Modes of Action for CBL0137, a Lead for Human African Trypanosomiasis Drug Development
(Your Name) has forwarded a page to you from Molecular Pharmacology
(Your Name) thought you would be interested in this article in Molecular Pharmacology.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleArticle

Polypharmacology of CBL0137 in the African Trypanosome

Carlos E. Sanz-Rodríguez, Benjamin Hoffman, Paul J. Guyett, Andrei Purmal, Baljinder Singh, Michael P. Pollastri and Kojo Mensa-Wilmot
Molecular Pharmacology July 1, 2022, 102 (1) 1-16; DOI: https://doi.org/10.1124/molpharm.121.000430

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Research ArticleArticle

Polypharmacology of CBL0137 in the African Trypanosome

Carlos E. Sanz-Rodríguez, Benjamin Hoffman, Paul J. Guyett, Andrei Purmal, Baljinder Singh, Michael P. Pollastri and Kojo Mensa-Wilmot
Molecular Pharmacology July 1, 2022, 102 (1) 1-16; DOI: https://doi.org/10.1124/molpharm.121.000430
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Methods
    • Results
    • Identification of CBL0137-Binding Proteins and Prediction of Biologic Effects of CBL0137 on Bloodstream T. brucei
    • Discussion
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • eCB Signaling System in hiPSC-Derived Neuronal Cultures
  • Benzbromarone relaxes airway smooth muscle via BK activation
  • Relapsed-leukemia model with NT5C2/PRPS1 hotspot mutations
Show more Articles

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About Molecular Pharmacology
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Journal of Pharmacology and Experimental Therapeutics
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0111 (Online)

Copyright © 2023 by the American Society for Pharmacology and Experimental Therapeutics