A natural product derived from bacteria has been found to inhibit the immune response in a more precise way, without interfering with the cell’s waste management processes.
The immunoproteasome plays a crucial role in the cellular immune response. However, in autoimmune disorders, this component is often excessively active. Until now, selectively inhibiting the immunoproteasome without impacting other cellular functions has been a challenge. Researchers led by Helge Bode have now developed a method to alter the production of a natural bacterial substance, leading to a novel and more specific medication. This advancement opens new avenues for targeted immunoproteasome inhibition.
The immune system needs to recognize the molecular composition of invading bacteria and viruses before it can act against them. To achieve this, a cellular enzyme complex called the immunoproteasome disassembles these intruders and presents their molecular makeup to immune cells. If the immunoproteasome becomes overactive and mistakenly attacks the body’s own structures, it can cause immune disorders. Researchers have long sought inhibitors for the immunoproteasome to help regulate this issue. However, it’s crucial that these inhibitors do not obstruct other proteasome variants vital for cellular recycling and waste management. Thus, ensuring drug selectivity is essential to minimize side effects.
The research team, led by Helge Bode at the Max Planck Institute for Terrestrial Microbiology in Marburg, has spent years designing enzyme complexes and employing synthetic biology to create innovative natural substances. Potential drug candidates for immune disorders, as well as antibiotics and anti-cancer drugs, come from both peptides and a group of long-chain fatty acids known as polyketides. Peptides are typically produced by non-ribosomal peptide synthetases, while polyketides originate from polyketide synthases.
Combining Enzymes
Recently, in partnership with Michael Groll from the Technical University of Munich and Markus Kaiser from the University of Duisburg-Essen, the team successfully created a peptide-polyketide hybrid through a streamlined process. “The XUT technology we developed utilizes docking sites found in thiolation domains. As these domains are common to both non-ribosomal peptide synthetases and polyketide synthases, it allows us to fuse enzymes for both types,” explains Leonard Präve, the lead author of the study.
Nature itself produces such hybrids of non-ribosomal peptide synthetases and polyketide synthases. For instance, a specific class of compounds called syrbactins, which are found in bacteria that affect plants or insects, work by inhibiting the proteasome in these organisms, effectively causing cell death by overwhelming their waste management systems.
This effect is advantageous in cancer cells, making syrbactins a potential avenue for cancer treatment. While proteasome-inhibiting drugs already exist, there hasn’t been a specific agent targeting the immunoproteasome with minimal side effects, particularly one based on syrbactin. “With our approach, we can thoughtfully modify syrbactins through several steps to develop a new, more selective inhibitor of the human immunoproteasome,” says Helge Bode. Although the compound created at this stage is not yet fully selective, it serves as a foundation for further refinement to enhance its effectiveness and reduce side effects. Future iterations will be optimized using computer simulations and high-throughput methods, allowing for the selection of the best candidates for specific uses.
