For the scientific community, the protein POP (prolyl oligopeptidase) is an attractive therapeutic target for the treatment of cognitive and neurodegenerative disorders.
Scientists at IRB Barcelona have developed the first POP inhibitors that are irreversible, selective and brain-permeable.
An article published in Cell Chemical Biology by scientists at the Institute for Research in Biomedicine (IRB Barcelona) describes a new class of prolyl oligopeptidase (POP) inhibitors. Found mostly in the brain, POP has emerged as an “attractive·” therapeutic target for the treatment of several cognitive and neurodegenerative disorders, such as Parkinson’s disease and schizophrenia.
Most POP inhibitors developed to date have a short half-life in blood, do not show sufficient selectivity for the protein, and do not cross the blood-brain barrier (which protects the brain), thus limiting their potential as drugs.
Work done by IRB Barcelona postdoctoral fellow Salvador Guardiola describes the first class of POP inhibitor characterised by long half-life, selectivity and capacity to enter the brain. The Design, Synthesis and Structure of Peptides and Proteins lab, headed by Ernest Giralt, has generated and characterised a family of 15 modified peptides (small proteins), called peptidomimetics, which have shown promising results.
"Natural peptides are not stable in tissues and have relatively weak activity. In contrast, if we modify them with synthetic amino acids and introduce functional groups designed to react with the therapeutic target, we can achieve peptides that are much more active and efficient," explains Guardiola.
At low concentrations, these new peptides inhibit POP in a rapid, specific and sustained manner, both in the isolated enzyme and in human intact cells. In addition, they are highly selective for two proteases that are similar to POP (DPPIV and FAP) and show a high capacity to cross the blood-brain barrier, say the researchers.
"These inhibitors pave the way for the development of new treatments for diseases of the central nervous system and will also contribute to studies on the role of POP in these disorders and to the development of inhibitors of other proteases," explains Giralt, who is also a senior professor at the University of Barcelona (UB).
This study has been funded by the Ministry of Economy and Competitiveness, ERDFs, and the Catalan government. It has involved the UB’s Nuclear Magnetic Resonance Unit, IRB Barcelona’s Mass Spectrometry and Proteomics Facility, and the Barcelona Supercomputing Center. The work was done in collaboration with scientists at the University of Glasgow (Scotland, UK), the Utrecht Institute for Pharmaceutical Sciences (the Netherlands,) and the biotech Iproteos, a spin-off from IRB Barcelona and the UB.
More about Ernest Giralt's research: "The power of the medicinal chemistry" - Meet Our Scientists
Reference article:
Salvador Guardiola, Roger Prades, Laura Mendieta, Arwin J. Brouwer, Jelle Streefkerk, Laura Nevola, Teresa Tarragó, Rob M. J. Liskamp, Ernest Giralt
Targeted covalent inhibition of prolyl oligopeptidase (POP): discovery of sulfonylfluoride peptidomimetics
Cell Chemical Biology (2018) DOI: 10.1016/j.chembiol.2018.04.013
RNE's "Inquietamente" programme has interviewed Meritxell Teixidó, IRB Barcelona research associate, about the study based on scorpion venom. "We saw that there was a peptide in the scorpion venom, chlorotoxin, which has the ability to reach the central nervous system and then act as toxin, "said Teixidó.
Link to RNE
TV3, RAC1, ABC, World Pharma News, Neuro Science, among other national and international media, have published articles about the research from the Peptides and Proteins Lab at IRB Barcelona. The study in question is inspired on the scorpion venom to deliver medicines to brain. The scientists have modified a peptide from the venom and used it as a shuttle to transport drugs across the barrier that protects the brain.
Link to TV3
Researchers at IRB Barcelona modify chlorotoxin—a small protein present in scorpion venom with blood-brain barrier permeability—to transport drugs into the brain.
The barrier, which protects the brain, prevents drugs used for the treatment of neurological diseases and brain tumours from entering the organ.
