A groundbreaking study has revealed that ribosomes, the essential molecular machines present in all living organisms, can now synthesize cyclic peptides with five- and six-membered rings. Now a research team led by Professor Joongoo Lee has made an important breakthrough. This new discovery is a seminal advance in the protein synthesis & drug design industry. Those findings were recently published in the highly-acclaimed journal Nature Communications.
Ribosomes have long been known as the “protein factories” of life. Ever since the very first life on our planet, they have historically created long, linear structures. In the past, these molecular machines were only able to link about 20 amino acids per second. This incredible pace is many orders of magnitude faster than traditional chemical synthesis approaches. Until now, however, the ability to produce such ring-shaped backbones proved elusive. The research team’s creative, groundbreaking approach has paved the way for next-generation drug design. They have increased the repertoire of cyclic peptides that ribosomes are able to generate.
Advancements in Ribosomal Synthesis
The recent study represents an incredible feat in ribosomal synthesis, and the researchers engineered 26 custom-designed amino acids. We ended up doing this without changing the ribosome expectation. Rather, we took advantage of its intrinsic processes in a benign biological context at 37°C and pH 7.5. This approach initiated some of the incredible development of both five-membered and six-membered securities. This was a phenomenon scientists had never seen despite billions of years of ribosomal evolution.
This was originally created by the Professor Lee’s group, when they first demonstrated the capacity for ribosomes to synthesize proteins containing six-membered rings in 2022. This prior discovery set the stage for what researchers recently found. Recently, some of these bottlenecks have been cleared as researchers have produced robustly complex cyclic backbones via ribosomes in vitro. There’s more to why this achievement is so impressive. Ribosomes are complex nano-size factories made out of nearly 4500 components that work together to carry out intricate molecular tasks.
The implications of this research are far-reaching. By allowing the synthesis of non-canonical cyclic backbones, this impactful work opens up the landscape for creating new therapeutic agents. The unpredictable nature of cyclic peptide generation would result in unique drug candidates with higher efficacy and specificity.
Collaborative Efforts
Alongside POSTECH, the U.S. Northwestern University and the University of Texas played important roles in this multi-institutional collaborative effort. This and other projects within this partnership underscore the power and potential that resides in interdisciplinary collaboration toward advancing scientific knowledge and innovation. The combined experience of these agencies played a huge role in getting this research project off the ground.
The results extend the limits of ribosomal production. In addition to making a compelling case, they showcase the exciting potential cutting edge research holds to create real-world applications that could revolutionize medicine. As scientists push to unveil the ribosome’s full toolkit, the potential for more effective, next-generation drugs grows even more exciting.
Implications for Drug Design
The potential to produce cyclic peptides using ribosomes would represent a paradigm shift in drug development. Cyclic peptides provide exceptional stability and bioactivity. This unique biology not only bestows them with a unique look, but makes them incredibly promising candidates for therapeutic applications. Now, by taking advantage of ribosomal synthesis, scientists can make better drugs with less side effects.
The implications reach far beyond drug design, potentially impacting multiple areas of the broad fields of biochemistry and molecular biology. We knew that researchers were rethinking their tools and methodologies. Such advancements may greatly change how peptides are synthesized, scaled, used, and applied to therapeutics, vaccines, and diagnostics.