Discovery of synthetic flavonoids for the treatment of corneal injury

ABSTRACT The cornea is an optically clear tissue that forms the front surface of the eye and accounts for nearly two thirds of its refractive power. Corneal trauma/injury is a main cause for blindness worldwide. The current standard of treatment, corneal transplantation, remains compromised by donor shortages and significant risks such as infections and transplant rejection. The majority of corneal blindness is permanent due to scarring/fibrosis; therefore, controlling the progression and state of scarring is crucial for the maintenance of vision. Surgical techniques are improving; however, these procedures are very invasive and may have long-term complications. Thus, there is a need for therapeutic interventions to reduce the need for corneal transplantation. Our group, previously showed that a naturally occurring flavonoid, Quercetin, can regulate corneal fibrosis, extracellular matrix assembly, and cellular metabolism. During our preliminary studies we investigated several commercial Quercetin analogs and their ability to modulate corneal fibrotic and DNA repair markers. Subsequently, we designed, synthesized, and tested seven novel synthetic flavonoids (sFNs) based on two different Quercetin analogs. The goal of the proposed studies is to determine whether such novel sFNs can be discovered that possess superior properties compared to naturally occurring flavonoids and are effective in mitigating or even reversing corneal fibrosis. We propose one, targeted, and highly translational specific aim where we will employ an iterative optimization process of design, synthesis, and evaluation to discover new sFNs that can be employed to determine whether sFN treatment can significantly impact (reverse and/or prevent) corneal fibrosis. If successful, the proposed studies will provide strong data, and justification, for future evaluation of our compounds in live animal models with a goal to delineate the effects on corneal fibrosis. In addition, successful completion of the proposed studies will justify and set the stage for continued drug discovery and development efforts to advance sFNs as novel therapeutics for the ocular injuries/trauma.