Identification of Cytoprotective Small-Molecule Inducers of Heme-Oxygenase-1

• Main Authors: Gelare Ghajar-Rahimi (Author), Amie M. Traylor (Author), Bini Mathew (Author), James R. Bostwick (Author), N Miranda Nebane (Author), Anna A. Zmijewska (Author), Stephanie K. Esman (Author), Saakshi Thukral (Author), Ling Zhai (Author), Vijaya Sambandam (Author), Rita M. Cowell (Author), Mark J. Suto (Author), James F. George (Author), Corinne E. Augelli-Szafran (Author), Anupam Agarwal (Author)
• Format: Book
• Published: MDPI AG, 2022-09-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Acute kidney injury (AKI) is a major public health concern with significant morbidity and mortality and no current treatments beyond supportive care and dialysis. Preclinical studies have suggested that heme-oxygenase-1 (HO-1), an enzyme that catalyzes the breakdown of heme, has promise as a potential therapeutic target for AKI. Clinical trials involving HO-1 products (biliverdin, carbon monoxide, and iron), however, have not progressed beyond the Phase ½ level. We identified small-molecule inducers of HO-1 that enable us to exploit the full therapeutic potential of HO-1, the combination of its products, and yet-undefined effects of the enzyme system. Through cell-based, high-throughput screens for induction of HO-1 driven by the human HO-1 promoter/enhancer, we identified two novel small molecules and broxaldine (an FDA-approved drug) for further consideration as candidate compounds exhibiting an E_max ≥70% of 5 µM hemin and EC₅₀ <10 µM. RNA sequencing identified shared binding motifs to NRF2, a transcription factor known to regulate antioxidant genes, including <i>HMOX1</i>. In vitro, the cytoprotective function of the candidates was assessed against cisplatin-induced cytotoxicity and apoptosis. In vivo, delivery of a candidate compound induced HO-1 expression in the kidneys of mice. This study serves as the basis for further development of small-molecule HO-1 inducers as preventative or therapeutic interventions for a variety of pathologies, including AKI.

Item Description

10.3390/antiox11101888
2076-3921