Bos, I. S.

Domling, A. S.

Gosens, R.

Groves, M.

Kema, I P

Kurhade, S. H.

Lunev, S.

Meurs, H.

Van den Berg, M. P.M.

van Faassen, H J

Zuidhof, A. B.

English

ARTS repository - University of Groningen

   University of GroningenExploring the in vitro and ex vivo efficacy of novel arginase inhibitors for the treatment ofallergic asthmaVan den Berg, M. P.M.; Kurhade, S. H.; Lunev, S.; van Faassen, H J ; Bos, I. S.; Zuidhof, A.B.; Groves, M.; Kema, I P; Domling, A. S.; Meurs, H.Published in:AllergyIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2018Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Van den Berg, M. P. M., Kurhade, S. H., Lunev, S., van Faassen, H. J., Bos, I. S., Zuidhof, A. B., Groves,M., Kema, I. P., Domling, A. S., Meurs, H., & Gosens, R. (2018). Exploring the in vitro and ex vivo efficacyof novel arginase inhibitors for the treatment of allergic asthma. Allergy, 73, 343-343.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.C74 ASTHMA: WHAT'S NEW IN ALLERGIC INFLAMMATION! / Thematic Poster Session / Tuesday, May 22/9:15 AM-4:15 PM/ Area A (Hall A-B2, Ground Level) - San Diego Convention CenterThe In Vitro and Ex Vivo Efficacy of Novel Arginase Inhibitors for theTreatment of Allergic AsthmaM. P. van den Berg1, S. H. Kurhade2, S. Lunev2, H. J. van Faassen3, I. S. Bos1, A. B. Zuidhof1, M.Groves2, I. P. Kema3, A. Dömling2, H. Meurs1, R. Gosens1; 1Molecular Pharmacology, Universityof Groningen, Groningen, Netherlands, 2Drug Design, University of Groningen, Groningen,Netherlands, 3Laboratory Medicine, University Medical Centre Groningen, Groningen,Netherlands.Corresponding author's email: m.p.m.van.den.berg@rug.nlRationale: Studies in asthma patients and animal models have shown a key role for arginaseisozymes in allergic airway inflammation, obstruction, hyper responsiveness and remodeling.Therefore, arginase represents a potential target for asthma treatment. The currently availablearginase inhibitors are not optimal for clinical development as they lack subtype selectivity, andshow limited uptake by cells and tissues due to the hydrophilic nature of the compounds. In thisstudy, we synthesized and pharmacologically evaluated the efficacy of a novel class of arginaseinhibitors. Methods: A colorimetric biochemical urea inhibition assay was used to generate IC50-values of the novel compounds for inhibiting recombinant human arginase 1 and 2 isotypes.Precision-cut lung slices of ovalbumin sensitized male guinea pigs were treated for 30 minuteswith the novel arginase inhibitors (1, 10 and 100 µM), or reference compounds Amino-2-Borono-6-Hexanoic Acid (ABH) or SHK145 (1 µM). Slices were used to establish ovalbumin doseresponse curves to examine the effect on airway narrowing. Furthermore, to examine the effect ofarginase inhibition on allergen induced histamine release, the ABH treated slices werestimulated with different doses of ovalbumin for 5 minutes. Slices were homogenized andhistamine levels of both homogenized tissue and supernatant were determined by HPLC-MS/MS. Results: IC50 determination for ABH, SHK145, SHK081-2, SHK081-5 and SHK186-8showed IC50-values of 1.5, 15, 19, 25 and 0.19 µM for recombinant human arginase 1 and 2.5,10, 20, 85 and 0.24 for arginase 2 respectively. Treatment of lung slices with 1 µM ABH resultedin a significant decrease in ovalbumin induced airway narrowing, decreased Emax and increasedEC50, compared to control. The efficacy of 1, 10 and 100 µM SHK081-2, SHK081-5 andSHK186-8 was comparable to that of ABH. Interestingly, slices pretreated with 1 µM SHK145showed a significant increase in Emax, but not EC50 or ovalbumin induced airway narrowing,compared to slices pretreated with 1 µM ABH (p < 0.05). Experiments to determine histaminelevels after ovalbumin challenge show a reduction in histamine release after treatment with 1 µMABH compared to control. Conclusions: We have shown that the novel compounds are able toinhibit the arginase enzymes in vitro and ex vivo in a similar fashion as ABH. Furthermore, weshow that arginase regulates allergic airway narrowing by influencing histamine release by mastcells. These findings bring us a step closer to the development of novel arginase inhibitors for thetreatment of allergic asthma.This abstract is funded by: STWAm J Respir Crit Care Med 2018;197:A5806Internet address: www.atsjournals.org  Online Abstracts Issue

Exploring the in vitro and ex vivo efficacy of novel arginase inhibitors for the treatment of allergic asthma

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Exploring the in vitro and ex vivo efficacy of novel arginase inhibitors for the treatment of allergic asthma

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