From slow to RaPID: The peptide discovery process

Reports claim that the development of peptide-based therapeutics, from discovery to commercial launch, can take approximately 10 to 15 years. Consequently, research has been centred around accelerating the prediction and discovery of promising peptides. Artificial intelligence (AI) is now one of the most promising tools. Algorithms such as AlphaFold can “predict the structure of proteins, deduce molecular interactions, and aid in the design of new drug candidates with desired specifications.”

But before the advent of AI, there was already a successful technology on the market. The random nonstandard peptides integrated discovery system, better known as RaPID, was developed over ten years ago by Hiroaki Suga, professor of chemistry at the University of Tokyo.

Hiroaki Suga, professor of chemistry at the University of Tokyo 

By integrating mRNA display with a set of flexible tRNA acylation ribozymes, the RaPID system effectively “prepares various libraries of natural product inspired macrocyclic peptides and rapidly screens highly potent ligands against various target proteins in an inexpensive manner.”

Tides Global spoke with Hiroaki Suga ahead of his presentation at TIDES USA in San Diego, California, to explore his contributions as a pioneer of accelerated peptide discovery.

What drew you to peptides as a drug modality?

I've been working in this field for a long time. I'm the person who invented the technology that displays macrocyclic peptides on messenger RNA (mRNA) - that's my expertise.

We're particularly distinct from others, not just in simple mRNA display. I also invented the technology to reprogram genetic code to incorporate various non-proteogenic amino acids, including D-amino acids and beta-amino acids. These are very difficult to incorporate using translation systems. We are the only laboratory that can really manipulate the genetic code as I described. No other laboratory has achieved this.

If you were explaining mRNA display to someone who is a novice in peptide research, how would you explain it?

mRNA display is the direct connection of the genotype, which is mRNA, to the phenotype, which is the peptide. This enables us to create over a trillion different sequences with automatic coding of the peptide sequence into messenger RNA.

The phenotype-genotype connection enables us to select for peptide activity while maintaining the ability to trace back to the genetic information through DNA transcription, PCR, and amplification of the signal. Even if we start from one sequence existing among a trillion different sequences, we can amplify the active sequence and generate thousands of copies. Then you proceed to another round of selection. It goes through approximately three to five rounds of selection to enrich the active sequence before moving to chemical synthesis.

How does the RaPID Platform work to improve the peptide discovery process?

With display, we can deal with a trillion different sequences at once and identify molecules in two weeks. It's a very fast process – I don't see any other technology that allows discovery at such a fast rate.

The RaPID system is the most robust and reliable method. Although this technology has been known for a long time, the way we developed it makes it more robust, reproducible, and reliable in many ways.

This system is a combination of mRNA display and genetic code reprogramming to express unique non-standard peptides. Since its development, the technology has been transferred to a company called PeptiDream, which I started over 18 years ago.

Their commercial name for it is Peptide Discovery Platform System (PDPS), but it's essentially the same thing. PDPS has been used for many drug candidates in collaboration with pharmaceutical companies such as Novartis, BMS, Genentech, Merck, Janssen, and others.

The technology was licensed to PeptiDream from the University of Tokyo. Since then, PeptiDream has sub-licensed it to other companies. Many companies are currently using the RaPID system to discover their own drugs.

It's a powerful tool that has been around for nearly 20 years. There has been much technological development during that time. Everyone in the field knows about it. Many copy companies have formed in the last three to four years as people anticipate patent exploration within five to ten years.

However, they don't have the technology for genetic code reprogramming, so they're still far from what PeptiDream is capable of. They're mostly just using display with biosystems and chemical cross-linking, similar to methods developed for phage display. They're basically mixing mRNA display and cross-linking, but this isn't the same as what PeptiDream can offer.

What are you most excited about that's coming down the pipeline in peptide therapeutics?

Several companies, including Merck and Janssen, are working on orally available macrocycles, which require significant medicinal chemistry work. Their starting point comes from molecules discovered using my RaPID system.

PeptiDream is really focused on radio therapeutics. They're working with radio-isotoping, which provides both diagnostic and therapeutic methods. Radiotherapeutics are becoming a powerful application for macrocyclic peptides.

The reason is that radioisotope therapy requires targeting specific cells, usually cancer cells. They target specific markers on cancer cells or tumors, and the isotopes destroy the target. However, unused compounds need to wash away quickly to avoid negative impacts. Fortunately, peptides are small enough to exit the body quickly. Unlike antibodies, this allows for a very fast attack and quick discharge.

Quotes have been lightly edited for clarity.