Chitin Analog AVR-25 Prevents Experimental Bronchopulmonary Dysplasia

Abstract

Infants born extremely preterm are at a high risk of developing bronchopulmonary dysplasia (BPD) which is characterized by large, simplified alveoli, increased inflammation, disrupted and dysregulated vasculogenesis, decreased cell proliferation, and increased cell death in the lungs. Due to lack of specific drug treatments to combat this condition, BPD and its long-term complications have taken a significant toll of healthcare resources. AVR-25, a novel immune modulator experimental compound, was able to partially recover the pulmonary phenotype in the hyperoxia-induced experimental mouse model of BPD. We anticipate that AVR-25 will have therapeutic potential for managing human BPD.

Chitin-Derived AVR-48 Prevents Experimental Bronchopulmonary Dysplasia (BPD) and BPD-Associated Pulmonary Hypertension in Newborn Mice

“…However, if prevented early, this condition can be mitigated to improve the respiratory status and developmental delays in childhood of these preterm infants. We have recently reported that AVR-48 decreases severe lung inflammation in LPS-, hyperoxiaand CLP-induced ARDS in adult mice while AVR-25, another close analog of AVR-48, can prevent lung injury in the neonatal mouse model of experimental BPD [19]. In order to facilitate bulk manufacturing, and improve physicochemical properties, we have optimized the chemical series and identified AVR-48 as a better lead than our previously reported compound, AVR-25.…”

“…After assessment of the safety profile of the AVR-48, and confirmation of t dose to be used, we next performed experiments to evaluate the therapeutic effec lungs in our experimental BPD mouse model, as previously described [19,[23][24][25] characterized by enlarged simplified alveoli with large air sacs, a thickened septu thin alveolar epithelium (Figure 2A), accompanied by an overall decrease in alve proliferation, decreased or dysregulated angiogenesis, and increased cell death. A features were restored after injection of two doses of AVR-48, IP (10 mg/kg) on and P4.…”

“…For the hyperoxia experiment, newborn pups were exposed to 100% hyperoxia (P0), along with their mothers, in cages in an airtight Plexiglas chamber (OxyCycler; Biospherix, Redfield, NY, USA) as described previously by us [19,24,34] for 4 consecutive days (till P4) and removed to RA on P5 to be recovered till P14, so as to emulate the human BPD condition. All pups were sacrificed on P14 for further experimental analyses.…”

“…Due to their natural occurrence, non-toxic nature, and biodegradability, low molecular weight natural oligosaccharides such as chitohexaose and one of its derivatives AVR-25, derived from chitosan and chitin polymers, have gained considerable attention as therapeutic candidates for multiple inflammatory diseases [19][20][21]. After conducting a medicinal chemistry campaign and structure-activity relationship study by screening >50 compounds, we identified a chitin analog AVR-48 (2S,3R,4R,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-2-(4-nitrophenoxy) tetrahydro-2H-pyran-3-yl) acetamide.…”

Chitin and Chitosan Derivatives as Biomaterial Resources for Biological and Biomedical Applications

“…Therefore, inhibition of chitotriosidase and acidic mammalian chitinase is regarded as a drug target for respiratory diseases [ 82 ]. However, it has been shown that a chitin analog AVR-25 partially alleviated pulmonary dysregulation in a hyperoxia-induced experimental mouse model of bronchopulmonary dysplasia by suppressing inflammation [ 83 ]. These findings indicate that chitin may have both beneficial and detrimental effects.…”