In recent years, the pharmaceutical industry has shown significant interest in improved alternatives to ‘small molecules’ for medication discovery. Within this strategic direction, cyclopeptidic compounds are gaining traction in drug discovery, medicinal chemistry, and materials science.
As explained by researcher Arkaitz Correa from the University of the Basque Country’s Faculty of Chemistry, unlike small molecules such as aspirin or ibuprofen, macrocyclic molecules are large molecular assemblies with high molecular weights, formed by the grouping of a wide variety of atoms. Specifically, macrocyclic peptides are composed of amino acids connected in a ring structure, meaning the ends of the amino acid chain are joined to form a cycle. These cyclic compounds have demonstrated unique properties compared to their linear (non-cyclic) counterparts, such as enhanced cell permeability, high thermal stability, and greater resistance to enzymatic proteolytic degradation. These pharmacokinetic advantages make them promising candidates as therapeutic agents, as they more effectively penetrate cells and are not rapidly degraded in the body.
Most cyclic peptides approved by the FDA for clinical use are derived from natural products, including antimicrobial agents and human peptide hormones. However, synthetic analogs of these compounds have also become widely used in chemical biology, especially for targeting protein-protein interactions that are difficult to modulate with small molecule drugs. Notable examples of cyclopeptides include vancomycin (a potent antibiotic), lanreotide (an anticancer compound), and gramicidin S, a historically significant cyclic peptide used for disinfecting bullet wounds during World War II. Despite their potential, the synthesis of cyclopeptides remains a major challenge due to their structural complexity.
The research group The Sustainable Catalysis: Methods and Computational at the University of the Basque Country has developed an innovative method for synthesizing cyclopeptides using sustainable catalysis. Their approach employs a low-cost copper salt and air as the oxidant, avoiding the use of toxic chemical oxidants and making the process environmentally attractive. Published in the prestigious journal ACS Catalysis, their method enables the preparation of a wide range of previously unknown cyclopeptide structures. Unlike natural cyclopeptides, which are composed solely of interconnected amino acids, their strategy incorporates a phenothiazine residue—a nitrogen-containing heterocycle with widespread medical use and luminescent properties—into the macrocycle. This residue’s propensity for oxidative processes allows it to form a cyclic structure through an intramolecular reaction with a tyrosine amino acid residue.
Through this approach, the research group has created a new family of cyclopeptidic compounds featuring a non-natural residue in their structure, potentially endowing them with novel and interesting properties. The team is collaborating with other research groups to investigate whether these new compounds possess luminescent properties and to explore additional methods for cyclopeptide synthesis. It is important to note that their group focuses primarily on basic research, developing new sustainable synthetic tools. Their work aims to design methods that either improve access to known compounds or, more often, make it possible to synthesize previously inaccessible molecules using traditional chemical synthesis strategies.
All in all, the research highlights the growing importance of cyclopeptides in modern drug discovery and the challenges associated with their synthesis. The development of sustainable and innovative synthetic methods, such as the one described by the University of the Basque Country team, opens new possibilities for creating cyclopeptides with unique properties, potentially leading to new therapeutic agents and materials. Fundamental research in this area continues to yield a wide array of novel chemical compounds with promising applications.
