Reactive oxygen species (ROS) are a heterogeneous group of highly reactive ions and molecules derived from molecular oxygen (O2), which can cause DNA damage and lead to skin cancer. NADPH oxidase 1 (Nox1) is a major producer of ROS in the skin upon exposure to ultraviolet light. Functionally, Nox1 forms a holoenzyme complex that generates two superoxide molecules and reduces NADPH. The signaling activation occurs when the organizer subunit Noxo1 translocates to the plasma membrane bringing a cytochrome p450 through interaction with Cyba. We propose to design inhibitors that prevent Cyba-Noxo1 binding as a topical application to reduce UV-generated ROS in human skin cells. 

Inhibitor design started from an apocynin backbone structure to generate a small molecule to serve as an anchor point, inhibitor 1, followed by adding a polyethylene glycol linked biotin in inhibitor 2. Further in vitro experiments using isothermal calorimetric (ITC) were used to quantify the binding affinity (KD). ITC and MALDI (TOF) MS was also used to show if binding of a Cyba peptide to Noxo1 was blocked. In vivo experiments were performed using donated skin explants with topical application of the two inhibitors while exposing the samples to UV. 

Inhibitors 1 and 2 were nontoxic in human cells, and successfully increased cell viability after UV exposure. Biophysical using ITC and MALDI revealed biotin as not necessary for inhibition while confirming affinity between inhibitor 2 and Noxo1. Further in vitro experiments using isothermal calorimetric binding quantification showed that inhibitor 2 bound a Noxo1 peptide with a KD of 2nM. Both using isothermal calorimetric binding and MALDI (TOF) MS showed that the binding of a Cyba peptide to Noxo1 was blocked. Experiments show that in primary skin explant models with ultraviolet light exposure, inhibitor 2 reduced the amount of cyclobutene pyrimidine dimers in DNA, a molecule known to lead to carcinogenesis. 

These findings demonstrate a novel inhibition of Nox1, which serves as a basis for further research to determine if this inhibitor can be added to topical sunscreens for public use in hopes of decreasing UVR-induced DNA damage and subsequent carcinogenesis. In addition, this novel sunscreen formulation could be a non-toxic alternative to chemical based barrier sunscreens that are currently on the market. 


Serendipitous Identification of a NOXO1 Inhibitor By Addition of a Polyethylene Glycol Chain

 Dermatology

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Serendipitous Identification of a NOXO1 Inhibitor By Addition of a Polyethylene Glycol Chain

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