The Power to Create Medicines That Reach Patients—Passing SHIONOGI’s Baton of Innovation to the Next Generation

Delivering medicines that society truly needs, with our own hands. This sense of pride and responsibility continues to drive SHIONOGI’s research laboratories. After 20 years of research, Takashi Kawasuji and his team succeeded in developing the HIV treatment dolutegravir. Shota Uehara, meanwhile, took on the challenge of creating the COVID-19 treatment ensitrelvir, taking a new approach. From the perspectives of both veteran and younger scientists, here we share the behind-the-scenes stories of drug discovery and how SHIONOGI’s “power to create medicines” is being handed down to the future.

Interviewer: Mr. Kawasuji, you spent nearly 20 years working on the discovery of dolutegravir. How did the project begin?

Kawasuji: When I joined SHIONOGI, the Shionogi Institute for Medical Science (now part of the Pharmaceutical Research Center) had already started research on HIV. Back in the early 1990s, when prejudice against AIDS was still prevalent, the first director, the late Dr. Yoshio Hinuma, Professor Emeritus at Kyoto University, strongly believed, “We must create medicines for patients.” I still remember how proud I was to be part of this project.

 

HIV mutates easily and quickly develops resistance, making it a very difficult virus to treat. Existing drugs with known mechanisms of action could not overcome this resistance problem, so we decided that a completely new type of drug was needed. SHIONOGI set its sights on targeting HIV’s third enzyme, integrase.

Interviewer: But at that time, wasn’t even the structure and activity of integrase still unknown?

Kawasuji: Exactly. It was an extremely difficult process, because we had to discover the science while simultaneously creating a drug. Integrase was notoriously difficult to handle. Even just developing an assay to measure its activity took about four years. Then, a handful of senior researchers manually screened 50,000 compounds over six months to find the first “hit compounds.” This effort was led by Tomokazu Yoshinaga, who became known as “Mr. Integrase.”

Interviewer: Screening 50,000 compounds by hand! So there were no High-Throughput Screening (HTS) robots yet?

Kawasuji: That’s right. I was amazed, too. Once we had hits, we gradually modified their structures to improve their potency and safety. After years of effort, we advanced the world’s first integrase inhibitor (S-1360) into clinical trials. Unfortunately, antiviral activity in humans was insufficient, and the program was halted in Phase 2. Still, this “world’s first” challenge caught the attention of GlaxoSmithKline (GSK), leading to a collaboration. It showed us that even a failed attempt can inspire others.

 

At SHIONOGI, we also had an original approach called the “two-metal model” for designing better integrase inhibitors, created by Ryuichi Kiyama. This unique method was another reason GSK was attracted to our work.

Interviewer: Did that collaboration bring success?

Kawasuji: Our next compound (S/GSK364735) showed clear antiviral activity in humans. But by then, competitors had developed once-daily integrase inhibitors. Ours required twice-daily dosing and did not offer an advantage against resistance, so we made the painful decision to abandon it. It was discouraging, but as researchers, we always strive for something better.

 

In parallel, we secretly pursued compounds with easier dosing and lower resistance risk. The result was dolutegravir. Since its launch in 2014, it has transformed HIV treatment, improving quality of life by reducing the chance of resistance. It remains a first-line treatment today, used by patients worldwide. Hearing doctors say “This is a good drug” has been one of my proudest moments.

Interviewer: What kept you going for 20 years without giving up?

Kawasuji: In research, failure is the norm. It wasn’t about grit or persistence alone. It was about working with my team toward “something better.” Even when results seemed invisible, motivated researchers came together, tackled the toughest problems, and even enjoyed the process. That spirit is what gives SHIONOGI its true strength in drug discovery.

Interviewer: Mr. Uehara, you contributed to the development of ensitrelvir using computational science, a new approach. How did this change the pace of drug discovery?

 

Uehara: Typically, drug discovery takes nine to 16 years. Ensitrelvir received emergency approval in Japan in just two years and five months. We didn’t skip any steps—the speed was enabled by computational science.

 

Virtual screening can replace months of High-Throughput Screening (HTS) with computer simulations to identify hit compounds. Ensitrelvir was SHIONOGI’s first successful case of drug discovery driven by virtual screening. It became a turning point in our computational science efforts.

 

Kawasuji: SHIONOGI had worked on computational science since its early days, though it couldn’t be practically applied at first. But the persistence to keep building the technology is what made this success possible. Beyond individual effort, the culture of supporting bold challenges allowed progress.

 

Uehara: Exactly. Years of refinement by our seniors, combined with breakthroughs such as AlphaFold2 (winner of the 2024 Nobel Prize in Chemistry) and advances in computing power, have changed the game. We can now simulate protein-compound interactions with remarkable precision across many targets. Computational science is finally making a real contribution to drug discovery.

 

Interviewer: Many imagine computational scientists as being glued to their PCs. How does your team actually work?

 

Uehara: We don’t just sit in isolation with data. Rather, we work closely with chemists and other departments. In fact, we share the same office as chemists, so we’re constantly discussing compound design and analysis results. Collaboration across specialties as one team was a key to success.

 

Kawasuji: That culture—no barriers between departments and constant learning from each other—is the secret to our innovation. With study sessions open to all, regardless of background, everyone shares a common understanding of drug discovery.

Interviewer: How exactly did you identify the hit compound that led to ensitrelvir?

 

Uehara: Under the leadership of Yuki Tachibana, then head of the infectious disease chemistry group, we targeted the 3CL protease (3CLpro), crucial for SARS-CoV-2 replication. Just three months after the emergence of COVID-19, we had already determined and published the structure of 3CLpro, enabling us to apply our structure-based drug design (SBDD).

To accelerate development, we virtually screened SHIONOGI’s internal compound library, which contained hundreds of thousands of molecules. Within days, we narrowed the list down to 300 promising candidates—among them, the seed for ensitrelvir.

 

Kawasuji: I recall seeing the simulation results and realizing the binding mode was unique. I thought, “This one will work.” It was deeply moving to see how far the technology had progressed. Years earlier, we had set up a rule to register all synthesized compounds in this internal library. It was tedious work, but we believed “every compound will someday become a future asset.” When that library proved invaluable during the pandemic, it was truly rewarding.

 

Uehara: That foundation was crucial. The hit compound already had well-established synthetic routes, combined with pharmacokinetic and safety data, giving us a major advantage.

 

In November 2022, ensitrelvir was granted emergency approval as a COVID-19 treatment—just two years and five months from the start of full-scale research. Without computational science and our internal library, such speed would have been impossible.

Interviewer: Only 0.005% of compounds ever become medicines. Yet SHIONOGI’s in-house discovery rate is 69%, far above the industry average in Japan. What is the source of this strength?

 

Kawasuji: Infectious diseases such as influenza and COVID-19 have enormous social impact and will never disappear as research targets. Through HIV drug development, I have listened to the struggles of patients—the constant reminder of illness with every dose, and the fear of stigma if their medicine is seen by others. Responding to such voices drives better therapies. Today, we are also developing long-acting injectable HIV drugs to address these concerns. The desire to deliver good medicines to patients is our greatest motivation.

 

Uehara: It all comes down to a strong determination to deliver medicines that society truly needs. Building on the success of ensitrelvir, our computational science team is working to establish even more advanced virtual screening methods. But that cannot be done alone—only with skilled chemists and teamwork can simulations become a reality. Looking ahead, we hope to expand into areas affecting quality of life, such as hearing loss and cognitive decline, where computational science can help untangle complex causes.

 

Kawasuji: Seeing younger colleagues like Uehara inherit our technology and spirit, and boldly take on new frontiers, reassures me that the future is in good hands. Drug discovery is about passing down passion and wisdom to the next generation. SHIONOGI’s strength will continue to deepen through this ongoing relay of innovation.