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New fluorination technology enhances therapeutic value of natural compounds

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Fluorination of therapeutic agents is a widely used strategy in the pharmaceutical industry. Allowing structural optimization of drugs considering the electronegativity and small size of fluorine improves drug molecular properties such as drug-target interaction, bioavailability and durability. The antidepressant Prozac, the cholesterol-lowering drug Lipitor, the antibiotic Ciprobay, and a quarter of the FDA-approved small molecule drugs contain at least one fluorine atom.

Natural compounds isolated from plants and microorganisms have evolved intrinsic abilities to interact with biological macromolecules, making them effective therapeutics. Adding a fluorine atom to a natural compound such as the antibiotic erythromycin makes the drug easier to reach the body and more effective against pathogens that have developed resistance to this antibiotic. Natural products are rarely fluorinated due to the lack of enzymes capable of adding fluorine atoms to natural compounds in .

The conditions required for these chemical reactions are often “harsh,” says Dr. Martin Grininger, professor of organic chemistry and chemical biology at Goethe University in Germany. “This means that there is a very limited choice of positions at which a fluorine atom can be attached.” Therefore, the need for new methods that can add fluorine to natural compounds is needed to develop effective therapeutics from natural substances. There is an urgent need to develop

In an article published in the journal entitled “Chemoenzymatic Synthesis of Fluorinated Polyketides” natural chemistryA team of scientists led by Dr. Gringer and David Sherman, professors of chemistry at the University of Michigan, reported the development of a chemoenzymatic method that can add fluorine atoms to natural compounds. In this method, we use an enzyme that acts as a gatekeeper for the precursor and engineer a precursor-resistant pinch to create a more promiscuous bacterial enzyme that accepts fluorine-containing reactants.

In this process, fluorine atoms are incorporated as part of small substrates during the biological synthesis of antibiotics. “Introducing the fluorination unit during the natural manufacturing process. This is an effective and elegant approach,” Grininger emphasized. “This gives us great flexibility in placing fluorine in natural substances, and we can influence their effectiveness.”

First authors and members of the Grininger team, Dr. Alexander Rittner and Dr. Mirko Joppe, inserted a subunit (acyltransferase domain) of an enzyme called fatty acid synthase into an evolutionarily related bacterial polyketide synthase. Fatty acid synthase is naturally involved in the biosynthesis of fat and fatty acids in mice, and is less selective about the precursors it processes, Rittner explained.

A hybrid enzyme combining bacterial polyketide synthase and murine fatty acid synthase utilizes fluoromalonyl coenzyme A and fluoromethylmalonyl coenzyme A as precursors during the chemical reaction that extends the polyketide chain, thereby producing their Fluorine can be introduced into the framework.

“The exciting part is that we were able to use erythromycin to fluorinate representatives of a huge class of substances called polyketides,” says Rittner. “There are about 10,000 known polyketides, many of which are used as natural medicines such as antibiotics, immunosuppressants and anticancer agents. Therefore, there is great potential for chemical optimization of this group of natural substances in antibiotics.”

Joppe believes this new method will also have an impact on the ongoing global battle against antibiotic resistance. “Research on antibiotics is not economically viable for a number of reasons. It is therefore the challenge of the university to fill this gap by working with pharmaceutical companies to develop new antibiotics,” Joppe said. “Our technology can be used to easily and quickly generate new antibiotics and now provides an ideal point of contact for projects with industrial partners.”

Grininger said: In collaboration with Professor David Sherman and his team at the University of Michigan in the United States, we plan to extend this new technique to include additional fluorine motifs. “

Rittner founded the startup kez.bisolutions to commercialize the new fluorination technology.