For many years, drug discovery was dominated by small-molecule compounds (approximately 500 Da). In the early 21st century, however, the successful development of macromolecular therapeutics, particularly antibody drugs (~150 kDa), stimulated strong interest in new classes of targeted therapeutics, referred to as new modalities. Dr. Hiroaki Suga initiated the development of molecular entities distinct from both small molecules and biologics well before these concepts became widespread, and proposed the concept of nonstandard peptide-based drug discovery, as described below.

1. Development of Flexizyme
Dr. Suga's work began with the development of an artificial RNA enzyme known as Flexizyme. Flexizyme is a ribozyme capable of acylating amino acids onto transfer RNA (tRNA); its name combines "flexible" and "ribozyme." Unlike canonical aminoacyl‑tRNA synthetases, Flexizyme can charge not only proteinogenic but also a wide range of non‑proteinogenic amino acids onto the 3′ terminus of tRNA with minimal substrate restrictions, thereby enabling their incorporation into the genetic code.

By applying this technology to the FIT (Flexible In vitro Translation) system, a cell‑free peptide translation platform, Dr. Suga's group achieved template‑directed in vitro synthesis of peptides containing diverse non‑proteinogenic amino acids that are otherwise difficult to introduce into peptide backbones.

2. Innovation in Special Peptide Drug Discovery
Building on pseudo‑natural peptide translation technology, Dr. Suga expanded his research to the discovery of macrocyclic peptides with molecular weights of approximately 1,500-3,000 Da. He established the RaPID (Random nonstandard Peptides Integrated Discovery) system, a platform that enables rapid and highly efficient identification of peptides with exceptionally high affinity for target proteins from libraries exceeding 10¹² members.

The RaPID system integrates genetic code reprogramming by Flexizyme with mRNA display, and is further enhanced by a spontaneous thioether‑based macrocyclization strategy. This approach enabled the discovery of peptide ligands against targets previously considered undruggable, thereby opening a new frontier in nonstandard macrocycles drug discovery. Today, macrocyclic peptide synthesis is a central theme in academic peptide research, and this global trend originated from Dr. Suga's work, whose impact has been profound.

These technologies were commercialized through PeptiDream Inc., a startup founded in 2006. Since around 2008, the company has collaborated with major pharmaceutical firms worldwide, translating the technology into practical drug discovery. PeptiDream was listed on the Tokyo Stock Exchange (currently the Prime Market), and Dr. Suga's RaPID technology (commercially known as PDPS) has been sublicensed to more than ten global pharmaceutical companies. His achievements span from fundamental research to innovation, making him a role model for researchers in the chemical sciences.

3. Expansion to Pseudo‑Natural Product and Neo‑Biologics Drug Discovery
In recent years, Dr. Suga has further extended the concept of special peptide drug discovery toward additional new modalities. Natural products include RiPPs (ribosomally synthesized and post‑translationally modified peptides) containing structural motifs such as azole rings and dehydroalanine, which cannot be directly introduced into peptide chains by genetic code reprogramming alone. Focusing on lactazole A (LazA), a representative RiPP, Dr. Suga combined its biosynthetic serine, threonine, and cysteine‑modifying enzymes with the FIT system to achieve one‑pot in vitro synthesis of RiPPs.

By integrating this approach into the RaPID system, he established a method to generate novel bioactive pseudo‑natural products from libraries of randomized LazA sequences. Although still at an early stage, this technology holds great promise for future pseudo‑natural product drug discovery.

Dr. Suga also elucidated that, in many cyclic peptide-protein interactions, only the internal pharmacophore sequence directly contributes to binding, while the thioether linkage that induces cyclization does not participate directly in target recognition. Nevertheless, macrocyclization itself is essential for high‑affinity binding. When such pharmacophore sequences are inserted into loop regions of proteins, they form pseudo‑cyclic structures that retain strong binding activity. This finding led to a groundbreaking protein‑engineering strategy whereby cyclic peptide motifs obtained from the RaPID system can be grafted onto proteins to confer new binding functions.

Dr. Suga termed the resulting class of engineered proteins "NeoBiologics", and has applied this strategy to antibodies, albumin, ubiquitin, capsid proteins, and others. Significant expectations are placed on the further development of NeoBiologics drug discovery.

In summary, Dr. Suga has been at the forefront of medium‑sized molecule drug discovery, pioneering the field of special peptide therapeutics. More recently, he has expanded his research into pseudo‑natural product and neo‑biologics drug discovery. His original and visionary contributions are widely recognized as highly deserving of the Chemical Society of Japan Award.