A novel CGRP-neutralizing Spiegelmer attenuates neurogenic plasma protein extravasation
| Autor: | Hoehlig, K, Johnson, K W, Pryazhnikov, E, Maasch, C, Clemens-Smith, A, Purschke, W G, Vauléon, S, Buchner, K, Jarosch, F, Khiroug, L, Vater, A, Klussmann, S |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Male
Time Factors Calcitonin Gene-Related Peptide Injections Subcutaneous Blood Proteins Aptamers Nucleotide Surface Plasmon Resonance Research Papers Islet Amyloid Polypeptide Rats Mice Inbred C57BL Rats Sprague-Dawley Mice Meninges Injections Intravenous Cyclic AMP Animals Humans Rats Wistar Half-Life |
| Popis: | Calcitonin gene-related peptide (CGRP) plays an important role in the pathology of migraine, and recent clinical trials suggest the inhibition of CGRP-mediated processes as a new therapeutic option in migraine. In this study, we describe the generation of NOX-L41, a CGRP-neutralizing mirror-image (L-)aptamer (Spiegelmer) and investigate its in vitro and in vivo function.A CGRP-binding Spiegelmer was identified by in vitro selection. Binding studies were performed using surface plasmon resonance (SPR), and the inhibitory activity was determined in cell-based assays. The pharmacokinetic profile comparing i.v. and s.c. dosing was analysed in rats. Intravital two-photon microscopy was employed to follow extravasation from meningeal vessels. Finally, in vivo efficacy was tested in a model of electrically evoked meningeal plasma protein extravasation (PPE) in rats.We identified NOX-L41, a novel CGRP-neutralizing Spiegelmer. SPR studies showed that NOX-L41 binds to human and rat/mouse CGRP with sub-nanomolar affinities and is highly selective against related peptides such as amylin. In vitro, NOX-L41 effectively inhibited CGRP-induced cAMP formation in SK-N-MC cells. In rats, NOX-L41 had a plasma half-life of 8 h. Pharmacodynamic studies showed that NOX-L41 extravasates from blood vessels in the dura mater and inhibits neurogenic meningeal PPE for at least 18 h after single dosing.This is the first description of the CGRP-neutralizing Spiegelmer NOX-L41. Preclinical studies confirmed a role for CGRP in neurogenic PPE and provided proof-of-concept for the potential use of this new drug candidate for the treatment or prevention of migraine. |
| Databáze: | OpenAIRE |
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