Loyola Researcher Publishes Paper on Multiple Sclerosis Drug

Researcher Valeria Pingitore, a scientist and professor of organic and pharmaceutical chemistry at Loyola University of Andalusia, has just published an article as first author in a prestigious journal. Science achievements about the development of a drug for the treatment of multiple sclerosis.

As Loyola Andalucía reports in a note, the results are based on preliminary studies. In the absence of further studies and clinical evaluations, this work could change the approach to treating neurodegenerative diseases, improving the quality of life of millions of people around the world.

The paper, titled “Delocalised Quinolinium Macrocyclic Peptides, an Atypical Chemotype for CNS Penetration”, is the result of research carried out by Dr Pingitore in the Drug Discovery Group at the Wolfson Institute for Biomedical Research, led by Professor David Selwood and affiliated with the Faculty of Medical Sciences at University College London – UCL (UK), one of the world’s leading universities.

Causes of sclerosis

Demyelination of nerve fibers is characteristic of multiple sclerosis and leads, among other things, to the formation of a mitochondrial permeability transition pore, the role of which is recognized as one of the key factors in the degeneration of neuronal axons, which causes this neurodegeneration.

One of the enzymes responsible for this process is cyclophilin D, a mitochondrial enzyme that is specifically localized in the brain, especially in the mitochondria of GABAergic interneurons and motor neurons. This enzyme is involved in the above-mentioned pore-opening process and therefore represents a suitable therapeutic target for the development of a drug capable of blocking the process of neurodegeneration in multiple sclerosis.

In this context, cyclosporine A is a macrocyclic undecapeptide drug that acts as an inhibitor of mitochondrial cyclophilin D, and although this inhibition has a marked neuroprotective effect, it is of no use in clinical practice because drug levels in the central nervous system are extremely low, even when the drug is administered by infusion.

Overall, these compounds can act on an increasingly wide range of therapeutic targets, but access to the central nervous system is still considered an unsolved problem due to the difficulty of penetrating the blood-brain barrier. This barrier is essential for protecting the brain, but it is an obstacle to the treatment of diseases of the central nervous system, as it hinders the penetration of most drugs.

Offer

The authors of the article proposed a structural modification of cyclosporin A by introducing a cationic fragment with a delocalized and shielded charge, which leads to an increase in mitochondrial accumulation of the drug and, in general, to better penetration into the central nervous system.

Therefore, in this study, the authors describe the design, chemical synthesis and biological evaluation of a series of molecules based on the cyclosporine A skeleton conjugated to delocalized quinolinium-type cations with inhibitory activity against mitochondrial cyclophilin D.

High concentration

Pharmacokinetic and metabolism studies show that this molecule reaches significant levels in the brain within 48 hours after a single dose, with brain concentrations approximately 20-fold higher than non-charge-delocalizing analogues or unmodified cyclosporine.

It is important to show that the application of this new technology, based on the synthetic introduction of a cationic moiety with a delocalized charge, can be applied to other drugs from the same family to provide them with access to the central nervous system.

Parkinson’s, ALS and Alzheimer’s Disease

Equally important, the use of cyclophilin D inhibitors is not limited to multiple sclerosis. Other indications include Parkinson’s disease, where genetic deletion of the enzyme delays the onset of the disease and extends the lifespan of Parkinson’s mouse models.

In amyotrophic lateral sclerosis (ALS), where its deactivation similarly delays disease onset and protects motor neurons, and in models of Alzheimer’s disease, where similar protective effects are observed. These findings reflect a common mechanism of mitochondrial dysfunction in these conditions.

A joint project

The project was carried out in collaboration with internationally renowned scientists associated with some of the most prestigious research centres and universities in the world, including the Centre for Neuroscience and Trauma (Blizard Institute, Queen Mary University of London, EPSRC National Crystallography Service (Department of Chemistry, University of Southampton, UK), the UCL Mitochondrial Research Consortium (UCL, UK), the Dipartimento di Scienze Biomediche dell’ Universitá di Padova (Padova, Italy), the UCL Infection and Immunity Unit – Faculty of Health Sciences (University College London, UK) and the International Collaboration on Repair Discoveries – Icord (University of British Columbia, Vancouver, Canada).

This study represents another starting point for the development of biomedical research at Loyola University. Valeria Pingitore is part of a team of scientists from different disciplines, such as medicine, biomedicine, quantitative methods and engineering, who work on the analysis of molecular mechanisms of diseases, as well as the identification and validation of biomarkers; the development of analysis methods and the integration of omics data, as well as the identification of therapeutic targets and drug development.