Corporate Banner
Satellite Banner
ADME Tox
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Synthetic Liver Enzyme Could Result in More Effective Drugs with Fewer Side Effects

Published: Tuesday, October 16, 2012
Last Updated: Tuesday, October 16, 2012
Bookmark and Share
Medicines could be made to have fewer side effects and work in smaller doses with the help of a new technique that makes drug molecules more resistant to breakdown by the human liver.

Researchers based at Princeton University reported in the journal Science that they created a synthetic enzyme that acts as a catalyst to replace certain hydrogen atoms of a drug molecule with fluorine atoms. This swap stabilizes the molecule and makes it resistant to the liver enzymes that can inactivate a drug or create toxic byproducts.

"Putting fluorine in place of hydrogen in a molecule tends to result in higher potency and lower toxicity," said first author Wei Liu, a graduate student in the laboratory of John Groves, Princeton's Hugh Stott Taylor Chair of Chemistry. Wei worked with Groves and second author Xiongyi Huang, a Princeton chemistry graduate student, as well as with Professor William Goddard III, researcher and lab director Robert Nielsen, and graduate student Mu-Jeng Cheng, all of the California Institute of Technology's Materials and Process Simulation Center.

Substituting fluorine for hydrogen changes the ability of liver enzymes to modify a drug, Groves said. Those enzymes break down medicines and other foreign substances that enter the body resulting in byproducts known as metabolites. Metabolites sometimes interact in harmful ways with liver cells and cause unwanted side effects. Fluorine reduces or eliminates the production of metabolites because the liver enzymes cannot break down the fluorinated drugs, Groves said.

"The strategy is to put fluorine at a site on the molecule where it would block metabolism by liver enzymes," Groves said. In some cases, he said, liver enzymes may not be able to break down the fluorinated drug at all, allowing more of the drug to persist in the body.

The synthetic enzyme could have uses in drug discovery and development including in improving existing drugs such as steroids, Groves explained. Steroids are used as anti-inflammatory drugs as well as in hormone-replacement therapies and birth-control pills. Steroid hormones that might be improved by fluorination include progesterone, premarin and estradiol, all of which are among the top 200 drugs in sales. The Princeton enzyme also could make it easier and less expensive to produce radioactive tracer versions of many drugs, which could be used with medical imaging to understand how and where drugs work in the body.

Tobias Ritter, a Harvard University associate professor of chemistry, said that the Princeton catalyst's novel abilities represent "a quantum leap in the fluorination field." Ritter is familiar with the study but had no role in it.

"The most exciting advance described in the paper is the fundamental reactivity of transforming carbon-hydrogen bonds into carbon-fluorine bonds using a fluoride-oxidant mixture," Ritter said. "Not only were chemists not able to perform such reactions in the past, we are not aware of similar reactions occurring in nature."

The catalyst Liu, Groves and Huang created breaks certain carbon-to-hydrogen bonds on pharmaceutical molecules and replaces the hydrogen with fluorine. Once the catalyst was developed, the Caltech group led by Goddard created computer models to explore its actions.

The synthetic enzyme is similar in structure to a naturally occurring iron-based liver enzyme called cytochrome P450, which normally replaces hydrogen atoms with oxygen atoms. The Princeton catalyst instead uses the metal manganese as a center atom. Because the manganese catalyst mimics the behavior of human liver enzymes, the compounds created when the catalyst is used in drug development are less likely to be broken down by those natural enzymes, Groves said.

The work grew out of the Groves' lab work on cytochrome P450. In 2010, Liu and Groves reported in the Journal of the American Chemistry Society the successful development of a synthetic manganese-based P450 that could replace hydrogen with a chlorine atom instead of an oxygen atom, which made drug molecules more reactive.

Suspecting that this catalyst could replace hydrogen with fluorine as well, Liu tested different fluorine-containing materials and eventually discovered that a combination of silver fluoride and tetrabutylammonium fluoride trihydrate led to drug fluorination. Huang isolated pure crystals of the manganese catalyst and assisted with modeling the molecule using computers.

An advantage for using the catalyst in drug development is that it uses a stable form of fluorine called silver fluoride as a base material instead of fluorine gas, which reacts with numerous other atoms and can be explosive.

"We can use ordinary fluoride salts, almost like the stuff that goes into toothpaste," Groves said.

The paper, "Oxidative Aliphatic C-H Fluorination with Fluoride Ion Catalyzed by a Manganese Porphyrin," was published Sept. 14 in Science, and was supported by grants from the National Science Foundation. The collaboration with Caltech stemmed from the Center for Catalytic Hydrocarbon Functionalization collaborative program funded by the U.S. Department of Energy.


Further Information

Join For Free

Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 3,200+ scientific posters on ePosters
  • More than 4,600+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Schmidt Fund Awards to Advance Innovations in Drug Therapy and Search for Planets
Two Princeton University research projects have been selected to receive grants from Princeton's Eric and Wendy Schmidt Transformative Technology Fund.
Friday, April 26, 2013
Scientific News
Rates of Nonmedical Prescription Opioid Use Disorder Double in 10 Years
Researchers at NIH have found that the nonmedical use of prescription opioids has more than doubled among adults in the United States from 2001-2002 to 2012-2013.
Self-Assembling Protein Shell for Drug Delivery
Made-to-order nano-cages open possibilities of shipping cargo into living cells or fashioning small chemical reactors.
Guided Chemotherapy Missiles
Latching chemotherapy drugs onto proteins that seek out tumors could provide a new way of treating tumors in the brain or with limited blood supply that are hard to reach with traditional chemotherapy.
What Makes a Good Scientist?
It’s the journey, not just the destination that counts as a scientist when conducting research.
‘Human-on-a-Chip’ Could Replace Animal Testing
Researchers are developing a “human-on-a-chip,” a miniature external replication of the human body, integrating biology and engineering with a combination of microfluidics and multi-electrode arrays.
A New Approach to Chemical Synthesis
Communesins, originally found in fungus, could hold potential as cancer drugs.
‘Missing Tooth’ Hydrogels Handle Hard-to-Deliver Drugs
Rice University’s custom hydrogel traps water-avoiding molecules for slow delivery.
Copper is Key in Burning Fat
Berkeley Lab scientist says results could provide new target for obesity research.
Better Animal Model to Improve HIV Vaccine Development
Penn study identifies a new tool to produce better HIV vaccine designs.
Identifying Side-Effects At Early Stages Of Drug Development
An approach that could reduce the chances of drugs failing during the later stages of clinical trials has been demonstrated by a collaboration between the University of Cambridge and pharmaceutical company GlaxoSmithKline (GSK).
Skyscraper Banner

SELECTBIO Market Reports
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
3,200+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,600+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!