New fluorination technology increases the therapeutic value of natural compounds

Fluorination of therapeutics is a widely used strategy in the pharmaceutical industry. It improves the molecular properties of a drug, such as B. Drug-target interactions, bioavailability and shelf life by enabling structural optimization of the drug due to the electronegativity and small size of fluorine. The antidepressant Prozac, the cholesterol-lowering drug Lipitor, the antibiotic Ciprobay, and a quarter of all small molecule drugs approved by the FDA contain at least one fluorine atom.

Natural compounds isolated from plants and microorganisms are powerful therapeutics because they have evolved an inherent ability to interact with biomacromolecules. The addition of fluorine atoms to natural compounds such as the antibiotic erythromycin makes the drug more accessible to the body and more effective against pathogens that have developed resistance to this antibiotic. However, natural products are rarely fluorinated due to the lack of enzymes that can add fluorine atoms to natural products in secondary metabolic reactions.

The conditions necessary for these chemical reactions are often “brutal,” said Martin Grininger, PhD, professor of organic chemistry and chemical biology at Goethe University in Germany. “This means that we are very limited in choosing the positions at which the fluorine atom can be attached.” The need for new methods that can add fluorine to natural compounds is therefore urgent to create effective therapeutics from natural substances to develop.

In an article titled “Chemoenzymatic Synthesis of Fluorinated Polyketides” published in the journal natural chemistry, reported a team of scientists led by Grininger and David Sherman, PhD, a professor of chemistry at the University of Michigan, on the development of a chemoenzymatic method that can be used to add fluorine atoms to natural compounds. The method uses an enzyme that acts as a precursor gatekeeper, developing a pinch of precursor tolerance to create a more promiscuous bacterial enzyme that accepts fluorine-containing reactants.

In this method, the fluorine atom is incorporated as part of a small substrate during the biological synthesis of an antibiotic. “We introduce the fluorinated moiety during the natural manufacturing process, an approach that is as effective as it is elegant,” emphasizes Grininger. “This gives us great flexibility in positioning the fluorine in the natural product – and we can influence its effectiveness.”

Lead authors and members of Grininger’s team, Alexander Rittner, PhD, and Mirko Joppe, PhD, inserted a subunit (acyltransferase domain) of an enzyme called fatty acid synthase into the evolutionarily related bacterial polyketide synthase. Fatty acid synthase is naturally involved in the biosynthesis of fats and fatty acids in mice and is not very selective in the precursors it processes, Rittner explained.

The hybrid enzyme combining bacterial polyketide synthase and mouse fatty acid synthase can use fluoromalonyl coenzyme A and fluoromethylmalonyl coenzyme A as precursors during the chemical reaction that elongates polyketide chains, introducing fluorine into their backbone.

“The exciting thing is that with erythromycin we were able to fluorinate a representative of a gigantic class of substances known as polyketides,” says Rittner. “There are around 10,000 known polyketides, many of which are used as natural remedies – for example as antibiotics, immunosuppressants or cancer drugs. Our new method therefore has enormous potential for the chemical optimization of this group of natural substances – in the case of antibiotics, above all to overcome antibiotic resistance.”

Joppe believes the new method will also impact the ongoing global fight against antibiotic resistance. “Research on antibiotics is not economically lucrative for various reasons. It is therefore the task of the universities to close this gap by developing new antibiotics together with pharmaceutical companies,” said Joppe. “Our technology can be used quickly and easily to generate new antibiotics and now offers ideal starting points for projects with industrial partners.”

Grininger: “We are testing the antibiotic effect of various fluorinated erythromycin compounds and other fluorinated polyketides. We intend to extend this new technology to other fluorous motifs in collaboration with Prof. David Sherman and his team at the University of Michigan in the United States.”

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

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