Novel method to design new peptide therapeutics pioneered

Hokkaido University researchers have developed a novel method to design and develop peptide antibiotics in large numbers, which will prove critical to controlling antibiotic resistance.

Microtiter plates that were used in the study for the assessment of antibiotic activity (Photo: Akira Katsuyama).

Applications of new molecules as drugs are expected to be effective in treating diseases that are difficult to cure with currently used conventional drugs. Peptides are one such type of molecule. They are well studied, and several drugs have been developed by the modification of different peptides. Modifying and testing new peptide structures is a time-consuming process, so any method that could reduce the time required for this process would rapidly accelerate drug development.

Researchers at Hokkaido University led by Assistant Professor Akira Katsuyama and Professor Satoshi Ichikawa at the Faculty of Pharmaceutical Sciences have developed a “scanning and direct derivatization” method for targeted modification of polymyxin, an antibiotic of last resort. Their work was published in the Journal of the American Chemical Society.

“Peptides are small molecules composed of amino acids, and are involved in many natural processes,” explains Katsuyama. “Due to how easy it is to modify them, peptides have great potential as drugs to treat diseases—modified peptides currently in use include drugs to treat diabetes, cancer, and other diseases.”

While the modification of peptides to enhance and alter their properties and biological effects is quite common, the process of making these changes in a targeted and deliberate manner is still very difficult. The research team approached this problem by modifying a technique known as peptide scanning, which is used to determine the role and importance of each amino acid in a peptide, to modify specific amino acids in polymyxin by the addition of different chemical groups.

The technique developed in the study involves modifying peptides at specific amino acids to confirm their functions (top), and then adding chemical groups to these amino acids to further alter and enhance their function (bottom) (Rintaro Kaguchi, et al. Journal of the American Chemical Society. January 28, 2023).

The team first designed a series of 12 scanning derivatives, and tested their antibiotic activity against 9 bacteria, including six highly virulent and antibiotic resistant bacterial pathogens. Based on their results, they chose three scanning derivatives for the further development for new antibiotic candidates that targets polymyxin-resistant Escherichia coli; and another four scanning derivatives to develop new narrow- and broad-spectrum antibiotic candidates.

The selected scanning derivatives were then subjected to direct derivatization. From the three selected to target E. coli, 324 derivatives were generated and tested for antibacterial activity; just four derivatives showed antibiotic activity comparable to polymyxin. In the assay of the narrow-spectrum derivatives, 10 out of 54 showed antibiotic activity against Pseudomonas aeruginosa comparable to polymyxin. Finally, for the broad-spectrum derivatives, just one out of 162 derivatives exhibited an antibiotic activity comparable to or stronger than that of polymyxin against all nine strains.

“We have shown that the technique we developed, the ‘scanning and direct derivatization’ protocol, can be used to generate and evaluate hundreds of peptide derivatives,” concluded Ichikawa. “We have also proven that it can be used to simultaneously develop derivatives with different effects. This method is widely applicable for the optimization of peptides.”

Rintaro Kaguchi (left), first author of the study, with Akira Katsuyama (center) and Satoshi Ichikawa (right), corresponding authors (Photo: Akira Katsuyama).

Published: 08 Feb 2023


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Content type: 

Rintaro Kaguchi, et al. Discovery of Biologically Optimized Polymyxin Derivatives Facilitated by Peptide Scanning and In Situ Screening Chemistry. Journal of the American Chemical Society. January 28, 2023.
DOI: 10.1021/jacs.2c12971

Funding information:

The study was supported by the Tukushi Fellowship and Research Foundation (Tukushi Scholarship); G-7 Foundation (G-7 Scholarship); Hokkaido University’s digital transformation (DX) Doctoral Fellowship; the Akira Matsuda Scholarship; the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant-in-Aid for Scientific Research (B) (22H02738, JP19H03345, JP21H03622), Grant-in-Aid for Scientific Research on Innovative Areas “Frontier Research on Chemical Communications” (JP20H04757), Grant-in-Aid for Early-Career Scientist (JP22K15241, JP19K16308); Platform Project for Supporting Drug Discovery and Life Science Research [Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)] from the Japan Agency for Medical Research and Development (AMED) (JP22ama121039, JP18ae0101047h0001, JP19ae0101047h0002, JP21ak0101118h9903); Japan Science and Technology Agency (JST) START Program (ST211004JO), JST SPRING (JPMJSP2119); North Tech Foundation; Takeda Science Foundation; and Hokkaido University Global Facility Center (GFC), Pharma Science Open Unit (PSOU) funded by MEXT under the “Support Program for Implementation of New Equipment Sharing System.”