The Quest for Selective Nox Inhibitors and Therapeutics: Challenges, Triumphs and Pitfalls

Significance: Numerous studies in animal models and human subjects corroborate that elevated levels of reactive oxygen species (ROS) play a pivotal role in the progression of multiple diseases. As a major source of ROS in many organ systems, the NADPH oxidase (Nox) has become a prime target for therapeutic development. Recent Advances: In recent years, intense efforts have been dedicated to the development of pan- and isoform-specific Nox inhibitors as opposed to antioxidants that proved ineffective in clinical trials. Over the past decade, an array of compounds has been proposed in an attempt to fill this void. Critical Issues: Although many of these compounds have proven effective as Nox enzyme family inhibitors, isoform specificity has posed a formidable challenge to the scientific community. This review surveys the most prominent Nox inhibitors, and discusses potential isoform specificity, known mechanisms of action, and shortcomings. Some of these inhibitors hold substantial promise as targeted therapeutics. Future Directions: Increased insight into the mechanisms of action and regulation of this family of enzymes as well as atomic structures of key Nox subunits are expected to give way to a broader spectrum of more potent, efficacious, and specific molecules. These lead molecules will assuredly serve as a basis for drug development aimed at treating a wide array of diseases associated with increased Nox activity.