Reviewing my postdoc years in Auckland

I have had the pleasure to be involved in writing a review paper with my colleagues at the Auckland Cancer Society Research Centre, New Zealand, during this year. And now that paper is out and it was actually published in very precious journal called Journal of Medicinal Chemistry. Our review of Small Molecule Inhibitors of Lymphocyte Perforin as Focused Immunosuppressants for Infection and Autoimmunity (link to the paper, open access) describes how cytolytic pore-forming perforin can be inhibited by small molecular weight compounds to treat different autoimmune diseases, since perforin, a protein that belong to our immune system, gets a bit carried way in several immunopathologies.

 

The paper nicely summaries what we were able to achieve in this field, of course, I was participating only a while, but it was great to put all the pieces together, memories those great years that we had in Auckland and also to summarize the work that I have continued here at the UEF, in Kuopio. Perforin inhibitors are not in the core of our studies anymore, but the compounds still have potential. Perhaps, some day we will see how they function towards a different target and in different indication. 😀

Introducing the new members of our increasing group

I guess it is time to introduce our new group members, well firstly one of them; Adéla Králová. This is what she wrote of her self.

Hi all, my name is Adela and I come from Czech Republic where I have just ended my Pharmacy studies. After graduation, I was lucky enough to know what I want to do in the future – mainly based on my previous ERASMUS experience at UEF. In September, I have joined a research group under the supervision of Kristiina Huttunen​ which is dealing with brain targeted therapy. Personally, I am focused on proteomics and the possibility to deliver creatine into neurons. It is an amazing opportunity for me to work and discuss about science with such a great community of researchers at School of Pharmacy. And as a bonus, I can explore Finland and do what I like the most in my free time - hiking and discovering new places on my own.

It is our pleasure to have you in our team, Adela. I hope we will have a fruitfull years ahead of us!

Interesting prodrug bioconverting enzyme paper out!

Hard work pays off! We have finalized one very interesting and also very important project, in which we were able to identify our L-type amino acid transporter 1 (LAT1)- utilizing prodrugs bioconverting enzyme from mouse brain. This was aminopeptidase B and it requires cobalt and slightly basic (ca. pH 8) conditions to be active and break down the amide bonds that we have in some of our prodrugs. We have long overlooked the amide prodrugs bioconverting enzymes, since we haven't had the right conditions in our in vitro studies to see any bioconversion, but we have seen the release of the active parent drugs in vivo and particularly in the mouse brain, so we have been confident that there is an enzyme for our prodrugs. Curiously, aminopeptidase B was more abundant in the brain than in plasma and liver, making it superior enzyme for brain-targeted purposes. In addition, we identified a bunch other good enzyme candidates for prodrugging and targeting prodrugs in the brain by global proteomic approach. 

The project itself was also a long one, I think we started it in autumn 2017 and many ERASMUS students were participating to this one. Therefore, I'm deeply thankful for all co-authors for their hard work and also everyone who has supported the study. The results were published in a special issue (Prodrug Design and Therapeutic Applications) of the journal called Frontiers in Pharmacology under a title "Aminopeptidase B can bioconvert L-type amino acid transporter 1 (LAT1)-utilizing amide prodrugs in the brain (link to the publication)".

And most importantly, the main conclusion of this stud was is that now we can design even better prodrugs bioconverted selectively by aminopeptidase B in the brain, in future.

Another research paper out

We have recently published a very interesting study, part of Ahmed's Ph.D. thesis, in which we administered one of our LAT1-utilizing anti-inflammatory prodrugs to mice and explored their behavior. This was a first study, in which we have proven that increased brain delivery and intrabrain delivery (into the microglia) of anti-inflammatory drug (salicylic acid in this case), alleviated the lipopolysaccharide (LPS)-induced neuroinflammation in mice measured as increased time the mice used in the rotarod and hanging tests. We also identified 399 proteins from the mouse brain by global (un-targeted) proteomic approach that were associated to neuroinflammation. Moreover, we noticed that several of those idenfied proteins were related to critical neuroinflammation pathways and affected by the prodrug treatment. Most importantly, we found that the LAT1-utilizing brain-targeted prodrug of salicylic acid decreased the cellular stress response and transmission across chemical synapses.

This paper was published in the journal called Life Sciences under the title "Enhanced drug delivery by a prodrug approach effectively relieves neuroinflammation in mice (link to the publication)"and it is published as open access. Well done Ahmed! Now we are waiting for you to finilize your Ph.D. thesis and to graduate!