The potential for OGG1 inhibition to be a therapeutic strategy for pulmonary diseases

ABSTRACT

Introduction

Pulmonary diseases impose a daunting burden on healthcare systems and societies. Current treatment approaches primarily address symptoms, underscoring the urgency for the development of innovative pharmaceutical solutions. A noteworthy focus lies in targeting enzymes recognizing oxidatively modified DNA bases within gene regulatory elements, given their pivotal role in governing gene expression.

Areas covered

This review delves into the intricate interplay between the substrate-specific binding of 8-oxoguanine DNA glycosylase 1 (OGG1) and epigenetic regulation, with a focal point on elucidating the molecular underpinnings and their biological implications. The absence of OGG1 distinctly attenuates the binding of transcription factors to cis elements, thereby modulating pro-inflammatory or pro-fibrotic transcriptional activity. Through a synergy of experimental insights gained from cell culture studies and murine models, utilizing prototype OGG1 inhibitors (O8, TH5487, and SU0268), a promising panorama emerges. These investigations underscore the absence of cytotoxicity and the establishment of a favorable tolerance profile for these OGG1 inhibitors.

Expert opinion

Thus, the strategic targeting of the active site pocket of OGG1 through the application of small molecules introduces an innovative trajectory for advancing redox medicine. This approach holds particular significance in the context of pulmonary diseases, offering a refined avenue for their management.

KEYWORDS:

• Epigenetic regulation
• OGG1 inhibitor
• NF-κB
• chronic lung inflammation
• airway remodeling

Article highlights

• Preclinical studies indicate the potential clinical relevance of highly selective small-molecule inhibitors targeting OGG1 in both acute and chronic airway inflammatory diseases.

• These OGG1 inhibitors decrease the expression of inflammatory and remodeling genes that harbor the epigenetic modification, 8-oxoGua, within their regulatory sequences.

• The interaction between OGG1 and 8-oxoGua induces alterations in the local DNA structure, thereby facilitating the binding of transcriptional effectors to DNA.

• Ogg1^−/− mice, which accumulate 8-oxoGua in DNA, show no symptoms, age normally, and become resistant to acute and systemic inflammation, indicating the potential dispensability of the mutagenic effects of 8-oxoGua.

• The targeted approach of using small molecules to inhibit OGG1’s active site shows promise in experimental models of asthma, COPD, pulmonary fibrosis, and acute airway infections.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

Conception and design: I Boldogh. Drafting the editorial article: L Pan. Critically revising the editorial article: I Boldogh. Reviewed submitted version of the manuscript: L Pan, I Boldogh. Article supervision: I Boldogh. Funding acquisitions: I Boldogh, L Pan.

Additional information

Funding

This work was supported by the National Institute of Allergy and Infectious Diseases under Grant [AI062885]; National Natural Science Foundation of China under Grant [31900424].