Is the drug development process cyclical

Macrocyclic Peptides: New Generation of Antibiotic Agents

Whether bacteria are resistant to antibiotics is often decided on their cell membrane. There antibiotics can be blocked on their way into the cell interior or catapulted from the inside out. Macrocyclic peptides, a new class of antibiotics, bioactive cell toxins and inhibitors, provide information about how this transport process takes place on the membrane, how it is influenced and how it can be used to circumvent the resistance of a malignantly transformed cell.

There are currently only a few synthetic active ingredients that bind to and block the widespread membrane transport proteins, the ATP binding cassette transporters (ABC). Scientists at Goethe University and the University of Tokyo have identified four of these macrocyclic peptides as models for a new generation of active ingredients.

Methods were used for which the participating scientists are considered to be world leaders. Thanks to deep sequencing, an extremely fast and efficient selection process, the desired macrocyclic peptides could be filtered out of a “library” of macrocyclic peptides comprising billions of variants - this number exceeds the number of stars in the Milky Way.

The fact that such an enormous number is actually available is due to a new type of process: By reprogramming the genetic code, amino acids can be used specifically as active ingredient components that are otherwise not used in the cell. They differ from natural proteins primarily in their circular, closed structure.

Peptides bring their “building instructions” with them

"Because these therapeutics are cyclical, they are broken down less quickly in the cell," explains Robert Tampé, director of the Institute for Biochemistry at Goethe University. "In addition, the ring-shaped active ingredients are limited in their spatial structure, so they bind to the target molecule without major rearrangements."

A third distinguishing feature makes the macrocyclic peptides particularly attractive for the scientists: When the active ingredients are manufactured, their assembly instructions are supplied as a “barcode”. If you look for certain ones from a number of billions of synthetically produced therapeutics, they carry their "name label" with them.

So what role do synthetic therapeutics play for antibiotic resistance in bacteria or multidrug resistance in tumor cells? What happens when they hit the ATP-driven transport molecule that is responsible for the resistance by carrying the chemotherapeutic drugs out of the cell?

In a nutshell: the active ingredients block the transporter by binding to it. This can be done at the beginning or at the end of a transport process when the transporter is idle. However, since the scientists can slow down the transport process so that it runs as if in slow motion, the active substances can be identified which “enter” in the middle of the transport process and “hold” the membrane protein in its respective position.

New ways for drug development

In this way, the researchers get an insight into the choreography of the transport process, like through the images of a film strip. These insights have already led to a “paradigm shift” in science, as Tampé explains: “So far we have assumed that ATP hydrolysis (note: an energy-releasing cleavage process) provides the energy for transport through the membrane. But this is only the case indirectly. It is the event of the binding of the ATP molecule that pushes substances out of the cell. The energy of hydrolysis, on the other hand, is used to restore the ABC transporter to its original state. "

The working groups at Goethe University and Tokyo University are convinced that these and other insights into membrane processes show ways in which future drugs can be developed.

Basic research on cellular membranes and membrane proteins has a long tradition in Frankfurt. Robert Tampé clarified essential mechanisms of ATP-driven transport proteins and cellular machines of the adaptive immune response and quality control, which together with the new publication can provide approaches for applied drug research.

After Tampé was the spokesman for the Collaborative Research Center “Transport and Communication via Biological Membranes” (SFB 807), which expired at the end of 2020, the concept for a new research center is already being developed. Highly dynamic processes in relation to protein networks and machineries in cellular membranes are to be researched. In the long term, the research results should reveal new possibilities for the therapy of molecular diseases, infections and cancer.

Source: Goethe University Frankfurt am Main

Publication: Robert Tampé et al .; De novo macrocyclic peptides dissect energy coupling of a heterodimeric ABC transporter by multimode allosteric inhibition; (20-02-2021-RA-eLife-67732)

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