We study targeted drug delivery

The name of your research group is Medicinal Chemistry and Drug Delivery. Can you explain what that means in more detail?

Most drugs used these days act systemically. This means they get distributed throughout the whole body according to their pharmacokinetic properties (the life of the drug in the body from administration to elimination), although this distribution may be somewhat uneven. Having a drug that can act throughout the body can be an advantage in some cases, for example when it comes to a viral infection, but if we are dealing with a disease in a particular location, such as a localized inflammation or tumour, it’s better to have a drug that acts solely in that specific location. This makes it possible to use lower dosages and therefore minimize side effects.

What exactly do you specialize in?

In our lab, we focus on targeted delivery of antifungals (antimycotic drugs) used to treat diseases caused by fungi, moulds and yeasts. The compounds we are working on have three components: a target recognition element, a linker, and the drug itself. The target recognition element is based on compounds like amphotericin B, nystatin or caspofungin, and it identifies and targets mycosis (a disease caused by fungi, moulds or yeasts). The drug is attached to the target recognition element through what we call a linker. When activation (breakdown) of the linker takes place, the drug is released only in the desired location, and that’s how we achieve the local effect. We are at an early stage of the research, currently exploring self-immolative phosphate linkers, which self-immolate (break down) on activation and release the drug very quickly. This kind of rapid release is important to prevent the drug from being carried away from the site of action.

How does the drug get activated? How exactly does the linker breakdown happen? 

We are predominantly focusing on enzyme activation based on substrate specificity. For example, amphotericin-based delivery identifies ergosterol in the fungal cell membrane, which is specific to certain fungal infections, because human cell membranes contain cholesterol. Once the target has been identified, the linker gets broken down through the action of certain enzymes, such as esterases or proteases, and the drug gets released at the site of action. We believe that amphotericin, which is an antifungal in its own right and disrupts the fungal cell membrane, will have a synergistic effect when combined with an additional drug.

So, to identify the target, you use substances that are drugs themselves? 

Yes, amphotericin and nystatin, for example, are antifungal drugs in their own right. And we connect another drug to them through the linker. This could ultimately reduce the concentration of the therapeutic agent required, and such therapy could be efficacious against multi-resistant mycoses, which are very problematic.

What is the competition in this field?

As far as I know, we are the only team specializing in targeted delivery of antifungals. But generally, targeted drug delivery is something that a number of labs are investigating, predominantly with regard to anticancer drugs.

Why did you decide to study this particular subject?

I became interested in self-immolative linkers while I was working at IOCB with Dr Gabriel Birkuš and Dr Zlatko Janeba several years ago. However, the focus on the project became less intensive over time, as we developed different ideas about it. I have now decided to take it further, though in a slightly different way – I have chosen a physico-chemical approach. I believe the key is to understand the mechanism of the self-immolative process. That’s why we are investigating photoactivatable linkers, which we measure via NMR, and that provides us with detailed data about their behaviour. We utilized the method of irradiating these couplings with UV light, directly in the NMR tube itself, and using phosphorus-31 spectroscopy which allow us to observe what happens to the linker following activation. This will help us understand the whole process and design optimal linkers for medical use.

And how did you get into antifungal research in the first place? 

There’s a rather interesting personal story behind it. My brother, who like me is a climber, came back from a mountaineering expedition in Nepal with a case of mycosis, which plagued him for a long time afterwards. It took almost a year before he was accurately diagnosed. No one seemed to know what to do with him. Eventually, it was a cardiologist from India who happened to make the right diagnosis during a cardiology examination. He said: “Wow, it’s Madura foot: I saw that back home in India.” Treating such diseases is very complicated, lengthy and can have a number of side effects. Drug resistance is also a serious problem. So, on this research topic, my motivation is also personal, and I believe that we will succeed in finding new therapies.

And does the start-up grant from the Experientia Foundation help you with that?

Yes, the start-up grant from the foundation helped me to obtain a post at Charles University and to set up my own research group. It allowed me to start working as an independent scientist and fully focus on what I enjoy.

You have had your own research group since January 2019. How do you rate the first year? 

I had no idea what it would involve. The first three months we were basically getting the lab set up and obtaining equipment. At the beginning, I really struggled with time management. There are really so many responsibilities. On top of the research itself and supervision of students, I am also kept busy teaching, preparing for classes and going to conferences. To all this you have to add the lectures, final exams, external examinations, and most of all, a huge amount of administration. Fortunately, things are running smoothly now; I have two undergraduates in the group, one Erasmus student, and one postdoc. But we are still open to new enthusiastic students.

Do you have any time left for science? And for your own research?

I try to make time for that: working in the lab is what I enjoy the most. I enjoy doing things that no one has done before and pushing the boundaries of human knowledge as part of a group of equally enthusiastic people. Playing. So I do find the time, but often at the expense of my personal life. And that’s why I try not to work at least one day a week.

You did your PhD as a member of Professor Holý’s group; what are your memories of that time? 

I met Professor Holý towards the close of his professional career. He was already suffering from some health issues, but he was still a huge personality and commanded respect. I remember doing my first chromatography. I was nervous and kept dropping things. He stood behind me, smiling with a hint of amusement. But it soon turned out that I did like chemistry and that I wasn’t totally clueless. He gave me my own project and that was great. Unfortunately, he died a year before I finished my PhD. During my PhD studies, I also met the second key figure in my scientific career, Petr Jansa, who is now a senior researcher at Gilead Sciences. Back then he was also studying for his PhD under the supervision of Professor Holý. He’s one of the best chemists I’ve ever met. He was a great motivation at the time.

Later, as a postdoctoral student, you joined Professor Potter’s group at the University of Bath. What did you get out of that experience? 

I gained a lot – both in my professional and personal life. You see, I left my family back in the Czech Republic – and I have two children. I was away for 15 months, which was definitely a challenge for my family life and relationships. But in the end, it made us closer. Professionally, too, I moved on significantly. Professor Potter is a world-class medicinal chemist, working on cell signalling and doing cutting-edge research, really state-of-the-art chemistry. He left the University of Bath for Oxford during my stay. His team was made up solely of postdocs and senior scientists, and that meant that I was surrounded by real experts, who have specialized in phosphate chemistry for most of their professional lives. I still keep in touch with them and we still have a very good relationship.

Were you thinking of staying in the UK? Or was your plan always to go back and set up your own group in the Czech Republic? 

No, it wasn’t as clear-cut as that. Professor Potter did offer me an extension of my stay at Oxford, but that also meant that I was faced with a choice between Oxford and my family. And I chose my family. I went back to Prague and joined Zlatko Janeba’s research group. For which I am very grateful: he gave me a degree of freedom, supported me and allowed me to move on. But it wasn’t an easy period for me. I wrote several grant applications, but all of them fell through. There were moments when I was thinking of giving up science altogether. But at the proverbial eleventh hour, I received this start-up grant from the Experientia Foundation, and a post at Charles University opened up at the same time, so things came together in an ideal combination.

What was your path to organic chemistry? Did you want to be a research chemist when you were young? 

I’ve enjoyed chemistry right from primary school, as we had a great teacher. The first class we had, he gave a demonstration: he sprinkled a mixture of sulphur and zinc onto a mesh above a Bunsen burner, and the reaction was like a tiny atomic mushroom cloud; then he did some volcanoes and a few similar showy demonstrations, and I began to suspect that chemistry might be the right thing for me. I went on to study chemistry at a specialist chemistry vocational school in Ostrava, and then on to university at the Institute of Chemical Technology in Prague.

What do you like about scientific work? 

I love the freedom the most. You can do “whatever you want”. But it comes at a price. I like it when you get a group of equally enthusiastic people together: there is a special energy to it – similar to the atmosphere you get with a tight band at a live gig, for example. Science is like a detective story: we keep searching and investigating. Every failure is a clue, a new set of information on how to arrive at the desired result.

What would be your recommendations to young scientists considering a scientific career? 

Find a good leader and a subject you enjoy working on. Stick with it, and don’t take failures personally. In the words of my former supervisor at the ICT: “Organic chemistry is a fight against perpetual failure. You have to learn how to improvise.” To make it in science, you also need some luck – being in the right place at the right time.

What do you do for fun outside research? What do you do in your free time?

I have a perfect family who are understanding of my work. So my free time I spend mostly with them and also sport climbing, which is something I can’t imagine being without. We love to be out there, on the rocks or in the mountains. So another recommendation would be to have a supportive family environment and to do some physical activity. This is the best way to relax, switch off your mind, and get away from the daily routine.