Pharmacological Screening Identifies SHK242 and SHK277 as Novel Arginase Inhibitors with Efficacy against Allergen-Induced Airway Narrowing In Vitro and In Vivo.

Arginase is a potential target for asthma treatment. However, there are currently no arginase inhibitors available for clinical use. Here, a novel class of arginase inhibitors was synthesized, and their efficacy was pharmacologically evaluated. The reference compound 2(S)-amino-6-boronohexanoic acid (ABH) and >200 novel arginase inhibitors were tested for their ability to inhibit recombinant human arginase 1 and 2 in vitro. The most promising compounds were separated as enantiomers. Enantiomer pairs SHK242 and SHK243, and SHK277 and SHK278 were tested for functional efficacy by measuring their effect on allergen-induced airway narrowing in lung slices of ovalbumin-sensitized guinea pigs ex vivo. A guinea pig model of acute allergic asthma was used to examine the effect of the most efficacious enantiopure arginase inhibitors on allergen-induced airway hyper-responsiveness (AHR), early and late asthmatic reactions (EAR and LAR), and airway inflammation in vivo. The novel compounds were efficacious in inhibiting arginase 1 and 2 in vitro. The enantiopure SHK242 and SHK277 fully inhibited arginase activity, with IC50 values of 3.4 and 10.5 µM for arginase 1 and 2.9 and 4.0 µM for arginase 2, respectively. Treatment of slices with ABH or novel compounds resulted in decreased ovalbumin-induced airway narrowing compared with control, explained by increased local nitric oxide production in the airway. In vivo, ABH, SHK242, and SHK277 protected against allergen-induced EAR and LAR but not against AHR or lung inflammation. We have identified promising novel arginase inhibitors for the potential treatment of allergic asthma that were able to protect against allergen-induced early and late asthmatic reactions. SIGNIFICANCE STATEMENT: Arginase is a potential drug target for asthma treatment, but currently there are no arginase inhibitors available for clinical use. We have identified promising novel arginase inhibitors for the potential treatment of allergic asthma that were able to protect against allergen-induced early and late asthmatic reactions. Our new inhibitors show protective effects in reducing airway narrowing in response to allergens and reductions in the early and late asthmatic response.

Novel biodegradable hydrogel sponge containing curcumin and honey for wound healing.

OBJECTIVE: To develop and evaluate a biodegradable superporous hydrogel based wound healing composite of chitosan and alginate incorporated with curcumin and honey. METHOD: A 3(2) factorial design was adopted to optimise the honey-curcumin hydrogel composite sponge (CHS). Sodium alginate and chitosan were dissolved in deionised water and 1% aqueous acetic acid solution at room temperature, respectively. Ethanolic solution of curcumin was poured into the chitosan solution followed by an addition of sodium alginate solution. In situ polymerisation was carried out by adding acrylamide base components to the polymeric solution of curcumin. Finally, honey was added with slow stirring and a sponge was cast on a glass surface by solvent evaporation at 45ºC. The produced sponge was assessed for swelling capacity, moisture loss, tensile strength, biocompatibility, bioadhesion, biodegradation, drug diffusion and wound healing properties. The morphology of CHS was studied by scanning electron microscopy (SEM). RESULTS: The optimised CHS demonstrated a high swelling capacity (111.05 ± 05%), tensile strength (4323gm/mm(2)), in vitro drug diffusion (75.03 ± 3.59%/20days), bioadhesion (20 ± 0.2mg force) and ability of water vapour transmission. A rapid induction of tissue granulation and re-epithelialisation was observed. Time to complete healing (94.14 ± 1.04% wound contraction) was 7 ± 2 days. CONCLUSION: This study has shown that honey-curcumin hydrogel composite sponge can be formulated by a simple mixing and in situ polymerisation method. The hydrogel base provided a dry wound bed due to excellent fluid absorption capacity. Chitosan and honey contributed to effective faster wound healing. We recommend further clinical studies of the soft sponge wound healing composite for diabetic foot or pressure ulcers.