The Department of Innovative Drug Discovery and Development (iD3) of AMED established Drug-Discovery Innovation and Screening Consortium (DISC) to accelerate the practical application of academic drug discovery research and bridge to pharmaceutical companies in 2015. DISC is an industry-academia open innovation initiative based on provided industry-original compound libraries from 22 pharmaceutical companies and high throughput screening (HTS). This program has many benefits for academia, for example, comprehensive drug discovery support (iD3 Booster), utilization of practical large-scale library and cutting-edge HTS equipment funded by AMED, and provision of licensing opportunities to pharmaceutical companies. In recent years, various improvements (DISC library expansion etc.) have been made. We hope that academia research will lead to breakthrough new drugs utilizing DISC.

Exscientia has been the world-leading Artificial Intelligence (AI) drug discovery company based in the UK since its establishment in 2012. Recently, we have delivered an IND from the collaboration with Sumitomo Dainippon Pharma, which was sensationally reported by many media in the world as the first AI-designed drug candidate. Our AI platforms cover not only multi-parameter-optimizing drug design but also predicting future trends of drug targets for disease of interest based on present available information. This article presents Exscientia’s cutting edge AI platforms as well as a view from the AI drug discovery frontline suggesting medicinal chemists inevitable to work with AI in the coming era.

Recently, a peptide with a molecular weight of about 500 to 2000 has received a great deal of attention as a new drug modality in the changing circumstances surrounding drug discovery. This special issue deals with the latest peptide synthetic chemistry that supports this peptide drug discovery. These are introduction of substrate-dominated reaction concept leading to innovation of peptide synthesis, new peptide synthesis using microflow chemistry, peptide synthesis using chemoselective ligation reactions with a scope toward protein synthesis, and artistic chemical synthesis of glycoprotein. All are written by researchers who are actively engaged in synthetic research using their own methodologies at the forefront of the field. I hope you will enjoy the latest peptide synthesis chemistry through this special feature.

Chemoselective ligations of non-protected peptide fragments have paved the way for chemical access to proteins, including native chemical ligation (NCL) which features the reaction of peptide thioesters with N-terminal cysteine peptides. Recently NCL allows for chemical synthesis of a wide variety of proteins over 150-residue with technical improvements relevant to the NCL being developed. Additionally, ligation protocols alternate to the NCL including Ser/Thr and KAHA ligations have also enjoyed success in protein chemical synthesis. Consequently, the chemical access to proteins has become within reach of researchers including organic and medicinal chemists. Herein, we briefly summarized the recent progress of chemoselective ligations for protein chemical synthesis.

Glycosylation is one of the most abundant post-translational modification of proteins. This process attaches oligosaccharides to proteins, resulting in glycoproteins. Although glycoproteins are involved in a variety of biological events, the function of oligosaccharides has been unclear due to the intrinsic heterogeneity in the oligosaccharide structure of native glycoproteins. To address this issue, we have explored chemical methodologies to synthesize structurally-defined forms of glycoproteins. In this essay, we describe recent examples of the total chemical synthesis of glycoproteins, enabling the study of the function of oligosaccharides on proteins at a molecular level.

Peptide drugs become increasingly important. In particular, specialty peptides including cyclic peptides and N-methylated peptides have garnered much attention in recent years. However, low cost production of these peptides has not been achieved. Nearly 140 years have passed since the first report of peptide bond formation by Theodor Curtius and numerous synthetic approaches have been developed for peptide syntheses. It seems like a very challenging task for making innovation in peptide syntheses. Micro-flow synthesis that uses thin channels as reaction space emerged in 1990’s. It provides new values for the uncontrollable reactions when using traditional batch reactors. Here, I introduce our amide bond formation using micro-flow technologies for accelerating innovation in peptide syntheses.

Unlike reagent controlled reactions (mechanism controlled reactions) which played significant role in organic synthesis in the past, substrate controlled reactions are relatively newer approach. Nevertheless, since its discovery the latter has become an indispensible tool in modern synthesis. In these reactions, an electron donor polar substituent in the substrate, namely a “directing group”, actively facilitates the transient interplay between the substrate and the reagent via nonbonding interaction, in such a fashion that the incoming group attacks stereoselectively. Thus the stereochemical outcome of a reaction is largely dependent on the nature of the substrate. I will describe our approach for the substrate controlled chemical reaction and its applications for peptide synthesis. Peptide synthesis is the most important research in this century for drug design and synthesis. The detailed background for this chemistry is described.

Phasing biology has recently been attracted attention as a new field of life science. Phasing biology focuses on the mesoscopic scale between biomolecules and cells. The droplets by liquid-liquid phase separation of proteins play an important role in various biological phenomena, including gene transcription and translation, protein folding, signal transduction, and intracellular quality control. In this article, I introduce the basic properties of liquid-liquid phase separation of proteins. Next, I discuss the function of small molecules in the presence or absence of protein droplets. Finally, I discuss how the amyloid hypothesis, which has been thought to be the cause of neurodegenerative diseases, should be reconsidered by Phasing biology for drug discovery.

An online symposium on “Synthetic organic chemistry: the young challengers” was held on July 31, which could not be held at the 140th Annual Meeting of the Pharmaceutical Society of Japan due to the spread of the COVID-19 infection. About 1,000 participants registered to attend the symposium, and four up-and-coming young researchers gave excellent lectures. This report describes the details of the event and what I learned through holding a symposium online.