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From mirror-image biology to enhanced therapeutic proteins

March 14, 2019

Scientists from the German Cancer Research Center (DKFZ) have succeeded in reconstructing biomolecules in their mirror-image form. The researchers' goal is to create a mirror-image artificial protein synthesis system. Their aim is to produce mirror-image therapeutic proteins, such as antibodies, which would be protected from biological breakdown in the body and do not provoke any immune response.

Almost all biological molecules exist as two different spatial structures that are related to each other like image and mirror image. These molecules are referred to as enantiomers. Much like one's right and left hands, they cannot be superimposed on each other. Depending on the direction in which the molecules rotate passing polarized light, they are termed D-enantiomers (to the right) or L-enantiomers (to the left). While almost all proteins found in nature are made up of L-amino acids, DNA and RNA are built from D-molecules.

Scientists from the German Cancer Research Center (DKFZ) in Heidelberg are working to synthesize biomolecules in their mirror-image form. In future, they intend to build more than single molecules: "Our long-term goal is to create simple, artificial biological systems in mirror-image form that corresponds to those in nature but do not interact with the environment," says project leader Jörg Hoheisel.

In their present work, the scientists led by Hoheisel have been able to generate a mirror-image version of a DNA-ligase from D-amino acids. Ligases join DNA fragments together. The mirror-image ligase can compose a complete mirror-image gene from equally mirror-image DNA fragments. More D-enzymes that replicate DNA and transcribe it into RNA are also already available. "This is as far as we have come for now," Hoheisel reports. "Next, we need a mirror-image structure that fulfills the function of ribosomes in the cell."

Ribosomes are macromolecular complexes in the cell which are responsible for translating RNA strands into chains of amino acids, thus producing proteins. "Once we have generated mirror-image ribosomes, we would have compiled a simple system that would allow us to produce any type of protein quite easily," said Hoheisel. "The artificial system would be independent of nature but identical in all biophysical and chemical characteristics and could ultimately lead on to an archetypical, mirror-image copy of a cell."

While this is still a vision of the more distant future, the underlying approach might already be used for therapeutic purposes in the near future, for example to synthesize mirror-image antibodies. Today, these therapeutic immunoproteins are produced synthetically and used as drugs to treat a number of diseases including cancer. However, the patient's immune system may produce bodily antibodies against the therapeutic antibodies. "For the body, they are ultimately foreign invaders which have to be fought, just like pathogens," Hoheisel explained. "An antibody drug consisting of mirror-image D-amino acids instead of natural L-amino acids would probably not provoke any immune response, because the immune system does not recognize D-molecules."

In addition, mirror-image antibodies could be therapeutically active for a longer time because they would be very slowly broken down biologically in the body. They could also be conveniently taken as pills since digestive enzymes in the body would not affect them. Hoheisel pursues these goals in an international collaboration with the support of the Federal Ministry of Education and Research (BMBF).
-end-
Source: Joachim Weidmann, Martina Schnölzer, Philip E. Dawson and Jörg D. Hoheisel. Copying life: synthesis of an enzymatically active mirror-image DNA-ligase made of D-amino acids. Cell Chemical Biology 2019, DOI: 10.1016/j.chembiol.2019.02.008

The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institute in Germany. At DKFZ, more than 1,000 scientists investigate how cancer develops, identify cancer risk factors and endeavor to find new strategies to prevent people from getting cancer. They develop novel approaches to make tumor diagnosis more precise and treatment of cancer patients more successful. The staff of the Cancer Information Service (KID) offers information about the widespread disease of cancer for patients, their families, and the general public. Jointly with Heidelberg University Hospital, DKFZ has established the National Center for Tumor Diseases (NCT) Heidelberg, where promising approaches from cancer research are translated into the clinic. In the German Consortium for Translational Cancer Research (DKTK), one of six German Centers for Health Research, DKFZ maintains translational centers at seven university partnering sites. Combining excellent university hospitals with high-profile research at a Helmholtz Center is an important contribution to improving the chances of cancer patients. DKFZ is a member of the Helmholtz Association of National Research Centers, with ninety percent of its funding coming from the German Federal Ministry of Education and Research and the remaining ten percent from the State of Baden-Württemberg.

German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)

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