Fluorination of therapeutic agents is a widely used strategy in the pharmaceutical industry. It increases molecular properties such as drug-target interactions, bioavailability, and durability by enabling structural optimization of the drug due to fluorines electronegativity and small size. Prozac, the cholesterol-lowering medication Lipitor, and the antibiotic Ciprobay, along with a quarter of all small-molecule drugs approved by the FDA, contain at least one fluorine atom.
Natural compounds that are isolated from plants and microorganisms are effective therapeutics because they have evolved an inherent ability to interact with biomacromolecules. However, natural foods are rarely fluorinated due to a lack of enzymes that can help add fluorine atoms to natural compounds in secondary metabolic reactions.
According to Martin Grininger, a professor of organic chemistry and chemical biology at Goethe University in Germany. This means that we are very limited in selecting the positions where the fluorine atom can be attached. This is especially the need for additional fluorine enhancements in natural compounds.
a team of scientists led by Grininger and David Sherman, a PhD, in Nature Chemistry, presented a chemical enzymatic technique capable of adding fluorine atoms to natural compounds. The technique employs an enzyme that acts as a gatekeeper for precursors and designs a pinch of precursor tolerance to form a more promiscuous bacterial enzyme that accepts fluorine-containing reactants.
During the natural production process, the fluorine atom is integrated as part of a thin substrate, thus we introduce the fluorinated unit during the natural production process, a method that is both effective and elegant, stressed Grininger. This allows us to have a greater flexibility when considering whether or not the fluorine is used.
Alexander Rittner, a PhD, and Mirko Joppe, a PhD, have all inserted a subunit (acyltransferase domain) of an enzyme called fatty acid synthase into the evolutionarily linked 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 chooses to process, Rittner said.
The hybrid enzyme that combines the bacterial polyketide-synthase and the mouse fatty-acid-synthase, can use fluoromalonyl coenzyme A and fluoromethylmalonyl coenzyme A as precursors during the chemical reaction that extended polyketide chains, thus incorporing fluorine into their structures.
According to Rittner, there are over 10,000 known polyketides, many of which are used as natural medicines, such as antibiotics, immunosuppressives, or cancer medications. Our new technique thus has a substantial potential for chemical optimization of this group of natural substancesin the antibiotics in order to overcome antibiotic resistance.
According to Joppe, the new approach will, in turn, impact the ongoing global battle against antibiotic resistance. Despite this, research on antibiotics is not economically lucrative. It is therefore the universities' responsibility to bridge this gap by developing new antibiotics in cooperation with pharmaceutical companies.
In collaboration with Prof. David Sherman and his team at the University of Michigan in the United States, Grininger said, We are studying the effectiveness of various fluorinated erythromycin compounds and additional fluorinated polyketides. This new technology will help the recipient with additional fluorine motifs.
Rittner has established the company kez.biosolutions, which aims to commercialize the new fluorination technology.