Skip to content
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Menu
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Menu
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Mitochondrial pyruvate carrier inhibitors improve metabolic parameters in diet-induced obese mice
Journal of Biological Chemistry, Volume 298, No. 2, Article 101554, Year 2022
Notification
URL copied to clipboard!
Description
The mitochondrial pyruvate carrier (MPC) is an inner mitochondrial membrane complex that plays a critical role in intermediary metabolism. Inhibition of the MPC, especially in liver, may have efficacy for treating type 2 diabetes mellitus. Herein, we examined the antidiabetic effects of zaprinast and 7ACC2, small molecules which have been reported to act as MPC inhibitors. Both compounds activated a bioluminescence resonance energy transfer–based MPC reporter assay (reporter sensitive to pyruvate) and potently inhibited pyruvate-mediated respiration in isolated mitochondria. Furthermore, zaprinast and 7ACC2 acutely improved glucose tolerance in diet-induced obese mice in vivo. Although some findings were suggestive of improved insulin sensitivity, hyperinsulinemic–euglycemic clamp studies did not detect enhanced insulin action in response to 7ACC2 treatment. Rather, our data suggest acute glucose-lowering effects of MPC inhibition may be due to suppressed hepatic gluconeogenesis. Finally, we used reporter sensitive to pyruvate to screen a chemical library of drugs and identified 35 potentially novel MPC modulators. Using available evidence, we generated a pharmacophore model to prioritize which hits to pursue. Our analysis revealed carsalam and six quinolone antibiotics, as well as 7ACC1, share a common pharmacophore with 7ACC2. We validated that these compounds are novel inhibitors of the MPC and suppress hepatocyte glucose production and demonstrated that one quinolone (nalidixic acid) improved glucose tolerance in obese mice. In conclusion, these data demonstrate the feasibility of therapeutic targeting of the MPC for treating diabetes and provide scaffolds that can be used to develop potent and novel classes of MPC inhibitors. © 2021 THE AUTHORS.
Authors & Co-Authors
Griffett, Kristine
United States, St. Louis
Washington University School of Medicine in St. Louis
Gill, Lauren E.
United States, St. Louis
University of Health Sciences and Pharmacy
Hegazy, Lamees S.
United States, St. Louis
Washington University School of Medicine in St. Louis
United States, St. Louis
University of Health Sciences and Pharmacy
Elgendy, Bahaa
United States, St. Louis
Washington University School of Medicine in St. Louis
United States, St. Louis
University of Health Sciences and Pharmacy
McCommis, Kyle S.
United States, St. Louis
St. Louis University School of Medicine
Finck, Brian N.
United States, St. Louis
Washington University School of Medicine in St. Louis
Statistics
Citations: 13
Authors: 6
Affiliations: 3
Identifiers
Doi:
10.1016/j.jbc.2021.101554
ISSN:
00219258
Research Areas
Noncommunicable Diseases