From the start of SynProAtCell, the team developed a groundbreaking set of chemical and cellular technologies that enable scientists to build, deliver, and study customized proteins directly inside living cells — something previously considered nearly impossible.
The first part of the project focused on developing new chemical techniques for assembling proteins with complete control over their structure and modifications. The team developed ultrafast, one-pot reactions that mimic nature’s ability to form complex protein linkages in minutes rather than days, as well as gold- and palladium-catalyzed reactions for connecting and folding peptides and proteins with remarkable precision. These advancements enabled the synthesis of proteins that were previously inaccessible, including those with multiple post-translational modifications such as ubiquitin and phosphorylation. Furthermore, these proteins were labeled with fluorescent dyes to monitor their cellular localization.
The next challenge was to introduce these synthetic proteins into living cells and observe their activity. To achieve this, the project developed innovative delivery strategies, including modified cell-penetrating peptides and bead-based physical loading methods, enabling several labeled proteins to enter cells simultaneously and remain functional. These approaches gave researchers, for the first time, the ability to follow the behavior of tailor-made proteins in real time within their natural cellular environment.
Using these methods, SynProAtCell uncovered new biological insights into the ubiquitin system—the cellular machinery that labels proteins for recycling or regulates their stability. The team discovered selective cyclic peptides that can modulate specific ubiquitin chain types and inhibit tumor cell growth, and revealed that the 20S proteasome can degrade ubiquitin together with its target proteins, challenging long-held assumptions about protein turnover.
All findings were shared widely through open-access publications, collaborations, and international conferences, and several of the developed methods are already in use by other research groups and industry partners.
Overall, SynProAtCell transformed the way scientists can study and manipulate proteins in living systems, establishing the foundation for a new era of chemically controlled biology with potential applications in medicine and biotechnology.
