Alexis Matralis Research Group

1)  Ongoing Projects

The circadian clock core component RORα as a novel target in Idiopathic Pulmonary Fibrosis (IPF). This is a collaborative project which combines the expertise of the host lab (Matralis’ lab) in Medicinal Chemistry with that of the collaborating labs in pathophysiology/animal modeling (Dr. Aidinis’ lab at Fleming and Professor Skarlatos Dendos, Faculty of Biology, Athens University) and translational medicine (Professor Katerina Antoniou, Faculty of Medicine, Crete University).

Idiopathic Pulmonary Fibrosis (IPF) is a chronic lung disease that is often fatal within 3-5 years after initial diagnosis. It is associated with increasing cough and dyspnea and impaired quality of life. IPF affects ∼5 million people worldwide, with incidence increasing dramatically with age. Despite extensive research efforts, its etiology in humans still remains elusive, reflecting to a significant health burden and unmet therapeutic need. Two small-molecule anti-fibrotic drugs, pirfenidone and nintedanib, have been recently adopted for IPF, however their low efficacy and side effects render them insufficient to successfully treat this disease. Preliminary results of our research team using specialized clinical lung tissue samples (Antoniou lab), underlined for the first time the cell-type dependent up-regulation of the mammalian core circadian clock component RORa receptor (retinoic acid orphan receptor alpha) in fibrotic lung tissues from IPF and cryptogenic organizing pneumonia patients. Consequently, the aforementioned clinical findings clearly suggest an important role for RORa receptor in IPF. Building on these results and extending our research on this field, the current research project intents to provide a robust evidence – proof of principle that RORa represents a crucial regulatory switch in IPF pathogenesis and an attractive therapeutic target that could be regulated by optimized and drug-like RORa ligands which are currently being made and tested (in vitro, in cells and in vivo) in the lab.

Development of novel Autotaxin (ATX) inhibitors with drug-like properties against idiopathic pulmonary fibrosis (IPF). This is a collaborative project with the group of Dr. Vassilis Aidinis at Fleming.

Long-term innovative research elegantly designed and conducted by Aidinis’ lab at Fleming in specialized experimental animal models and clinical tissue samples underlined the role of ATX and LPA as a driving force in the pathogenesis of IPF in both mice and affected patients. These experimental genetic and pharmacological studies provided the scientific basis for the regulatory and crucial role of ATX in IPF as well as the proof-of-principle for the development of ATX inhibitors for clinical and therapeutic applications. The present project concerns the pharmacological optimization of structurally new Autotaxin inhibitor leads, identified by applying cheminformatic tools and in vitro enzymatic assays. The aim of this approach is to appropriately tune the skeletal, substituent and conformational features of the new leads through application of a molecular diversity-oriented Structure-Activity Relationship (SAR) strategy. That part is accompanied by in vitro, ex vivo, Pharmacokinetic/Pharmacodynamic (PK/PD), toxicity and in vivo studies aiming at evaluating the bio-efficacy and safety profile of the best derivatives. In this context, our approach stands at the cutting-edge research for novel therapies against IPF and aspires to create promising novel advanced leads for clinical applications.

Drug repositioning application followed by Medicinal Chemistry approaches towards the development of new chemical entities for rheumatoid arthritis intervention. This is a collaborative project with the group of Professor George Kollias at Fleming and the CRO Company Biomedcode specialized in preclinical testing.

Drug repositioning is the process of redeveloping an already approved drug or abandoned compounds for use in a different disease. Drug repositioning is underpinned by the fact that common molecular pathways contribute to many different diseases, while it has many advantages over traditional de novo drug discovery approaches in that it can significantly reduce the cost and development time. It was found by applying bioinformatic tools that a known commercially available antipsychotic/antidepressant drug exhibits also a moderate but statistically significant activity in a rheumatoid arthritis mouse model. Using this drug as a starting point, our goal is to remodel its structure so as to refine those structural determinants providing potent anti-arthritis molecules with drug-like properties. This project is also multidisciplinary in nature, combining design, synthesis, chemoproteomics, phosphoproteomics and in vitro and in vivo pharmacological evaluation assays.

Highlighting the role of SRPK-2 protein kinase in developing a new generation of potent fast-killing antimalarial drugs. 

In collaboration with the laboratory of Professor David Baker at London School of Hygiene and Tropical Medicine (LSHTM) and the pharmaceutical industry GlaxoSmithKline (GSK), we have developed a novel series of antimalarial compounds exhibiting a new mechanism of action and an extremely fast-kill antiparasitic activity. Of note, the parasite killing rates of the most promising derivatives are similar to or even better than artemisinins, the best fast-kill drugs existing so far. In addition, chemoproteomic analysis highlighted for the first time parasitic serine/arginine protein kinase 2 (SRPK-2) as the main target of the novel chemotype. The most promising analogues of this series are now serving as: i) leads towards identifying novel antimalarial agents with new mechanisms of action and a strong fast-killing profile which are missing from the therapeutic arsenal against malaria, and ii) pharmacological tools to confer advances in understanding the mechanistic interrelationship among SRPK-2 inhibition, increasing fast-killing rates and implications for rational therapeutics for malaria.


2) Near-future Projects  

Targeted delivery of bioactive molecules to brain-mitochondria as a novel approach against Neurodegenerative Diseases.