Previous studies have shown the inhibitory properties of sweeteners, such as saccharin, to CA IX. In this study, the binding of the sweetener acesulfame potassium (Ace K) is compared between CA IX and other essential carbonic anhydrases in the body.
What did the Scientists Discover?
Using X-ray crystallography, a method that allows visualization of drug binding to enzymes, the crystal structures of CA IX and off-target CA II bound to Ace K were determined. This study demonstrated Ace K binds directly to CA IX whereas it binds through a water molecule in CA II. This observation may relate to why Ace K binds CA IX more effectively than CA II, and therefore represents a useful compound for inhibiting CA IX with fewer side effects.
Hence, this study contributes to the investigation of Ace K as a lead compound that can be used to design more specific CA IX inhibitors that would prevent the growth and metastasis of tumor cells.
Impact:
Breast cancer still kills nearly 40,000 women in America each year. Many of these cases are related to triple negative breast cancer (TNBC) because this is an aggressive subtype with no known targeted treatments. The observations of this research will help scientists design more specific drugs for the treatment of TNBC. Furthermore, the proposed lead compound, Ace K, is an FDA approved sweetener that has been proven safe for human consumption.
Collaborators:
Robert McKenna, University of Florida, Coll. Med. rmckenna@ufl.edu
Akilah Murray, University of Florida, Coll. Med.
Carrie Lomelino, University of Florida
Claudiu Supuran, University of Florence, NEUROFARBA
Publication citation:
"Seriously Sweet": Acesulfame K Exhibits Selective Inhibition Using Alternative Binding Modes in Carbonic Anhydrase Isoforms
By: Murray, Akilah B.; Lomelino, Carrie L.; Supuran, Claudiu T.; et al.
Publication: Journal of Medicinal Chemistry
Volume: 61
Issue: 3
Pages: 1176-1181
Published: Feb 8 2018
Funding:
Funding Agency |
Grant Number |
National Center for Advancing Translational Sciences of the National Institutes of Health under University of Florida |
TLITR001428 |
National Science Foundation |
DMR-1332208 |
National Institute of General Medical Sciences, National Institutes of Health |
GM-103485 |