While the Netherlands was in lockdown because of the coronavirus, PhD candidate Koen Rijpkema began his research into the same virus. In the lab, he developed molecules that can inhibit an important viral enzyme.
Rijpkema started his PhD in the middle of the pandemic, complete with lockdowns and curfews. 'I lived with seven other people, plus visiting partners. At one point I was in quarantine more often than not,' he says. Working from home was hardly an option, because his research depends heavily on lab experiments.
The coronavirus did, however, offer a highly relevant research topic. 'I really wanted to do a lot of synthesis: designing and making new molecules, ideally with the same supervisor I had during my master's project. He suggested looking for molecules that could inhibit the coronavirus. It was a timely and meaningful project.'
Tricking a virus
Rijpkema focused on a specific part of the coronavirus: an enzyme that suppresses the immune system. Normally, the immune system responds to a virus by releasing signaling molecules that 'raise the alarm' in the body. But this viral enzyme-called Mac1-removes part of such a signaling molecule, disrupting the signal and making it harder for the immune system to detect the infection.
The solution was to mislead the enzyme. 'We make molecules that resemble the part of the signalling molecule that Mac1 normally binds to. But our molecules bind much more strongly. In this way, we keep the enzyme busy with decoy molecules, so it can no longer bind to the real signalling molecules.' This allows the immune system to respond more effectively to the virus.
From scattered puzzle pieces to one strong molecule
But how do you actually design a molecule that fits? In this case, Rijpkema could not rely on computer models. 'We did try,' he says, 'but so little was known about the enzyme at the time that the models did not give any clear direction.'
Instead, it came down to trial and error. For each part of the molecule, Rijpkema and his colleagues had to design a synthetic route: a series of chemical reactions starting from simple building blocks that together produce the desired molecule.
'For the first two years, I basically only did things that didn't work.'
They then tested whether it worked, and adjusted it if it didn't. 'For the first two years, I basically only did things that didn't work.' But this process helped him discover which changes improved the molecule. 'In the end, we combined all the successful parts into one so-called "super molecule" that binds very strongly to the enzyme.'
'Another group just beat us to it'
Alongside challenging research, Rijpkema also faced tough competition. Just as he was ready to publish his first results, another study with similar findings appeared. 'After two and a half years we finally had something that worked, and then another group just beat us to it,' he says.
Rather than giving up, the team shifted their focus. 'We emphasised not the biological data, but the way we had made our molecules,' he explains. 'That was slightly different, and more elegant than what the other group had done.'
'It was a good learning moment. This is sometimes how science goes, but you have to be flexible and keep going.'
Decoy molecule as a stepping stone towards new medicine
The new decoy molecule is not a medicine in itself, but it is an important step forward. The molecules Rijpkema developed mainly help scientists better understand how the enzyme works.
That knowledge is crucial for pharmaceutical companies, which can use it to develop real treatments in the future. 'We do fundamental research,' Rijpkema says. 'But without that foundation, you cannot develop targeted medicines.'
Thesis and defence
Koen Rijpkema will defend his PhD thesis, Synthesis of ADP-ribose Analogues, on 16 April at the Academy Building. His supervisors are Dr Dmitri Filippov and Professor Jeroen Codée.
