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
In its “Preguntas Big Van” section, the newspaper La Vanguardia has interviewed IRB Barcelona researcher Meritxell Teixidó about her project, which seeks to develop “shuttles” that transport drugs into the brain. In this regard, 98% of drugs that start to be developed to treat diseases of the central nervous system are abandoned because they cannot cross the barrier that protects the brain. Inspired on bee and scorpion venom, Teixidó has identified several families of peptides capable of crossing this barrier.
Meritxell Teixidó, a researcher at IRB Barcelona, has been interviewed on the TVE2’s documentary ¡Qué animal! about her work with peptides from scorpion and bee venom in search of drugs that can reach the brain. "These poisons are able to reach the brain, which explains their toxicity. It is precisely this capacity that attracts us to examine their applications," explains Teixidó.
Link to TVE
It is estimated that one in four people will require brain treatment at some point. While there are drug candidates for most diseases of the brain, the blood-brain barrier (BBB) poses an impassable obstacle for most of these compounds and a bottleneck for the delivery of drugs that could cure these patients.
