AI Article Synopsis
- - A new series of molecules mimicking Pleiotrophin's effects in the central nervous system (CNS) has been developed to pass through the blood-brain barrier, targeting a specific protein called PTPRZ1.
- - The most effective compounds, 10a and 12b, enhance the phosphorylation of important proteins involved in neuron health and show protective qualities against damage from amphetamines.
- - In vivo tests confirmed that compound 10a can successfully cross the blood-brain barrier, suggesting potential for creating new treatments for CNS-related issues like drug addiction and neurodegenerative diseases.
Article Abstract
A new series of blood-brain barrier permeable molecules designed to mimic the activity of Pleiotrophin in the CNS has been designed and synthesized. These compounds exert their action by interacting with the intracellular domain PD1 of the Protein Tyrosine-Phosphatase Receptor Z1 (PTPRZ1), and inhibiting its tyrosine phosphatase activity. The most potent compounds 10a and 12b (IC = 0,1 μM) significantly increase the phosphorylation of key tyrosine residues of PTPRZ1 substrates involved in neuronal survival and differentiation, and display protective effects against amphetamine-induced toxicity. Docking and molecular dynamics experiments have been used to analyze the binding mode and to explain the observed selectivity against PTP1B. An In vivo experiment has demonstrated that 10a can cross the BBB, thus promoting the possibility of moving forward these candidates for the development of drugs for the treatment of CNS disorders, such as drug addiction and neurodegenerative diseases.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5817915 | PMC |
| http://dx.doi.org/10.1016/j.ejmech.2017.11.080 | DOI Listing |
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