Chlorhexidine as a Keap1-Nrf2 inhibitor: a new target for an old drug for Parkinson's disease therapy

Abstract

Oxidative stress plays a vital role in the pathophysiology of most neurodegenerative diseases such as Parkinson's disease (PD). The Keap1-Nrf2-ARE pathway, one of the internal defense mechanisms, curbs the reactive oxygen species (ROS) generated in the cellular environment. The pathway leads to the expression of antioxidant genes such as HO-1, GCLC, and NQO1, which act as cellular redox switches and protect the cellular environment. Keap1, the negative regulator of Nrf2, is a potential therapeutic target for treating age-related neurodegenerative diseases. Tecfidera (Dimethyl fumarate), used in the intervention for relapsing multiple sclerosis, is the only commercial drug known to regulate the Nrf2 function. Here, we have identified a repurposing drug, chlorhexidine (LBP125), through ligand-based pharmacophore development and screening against the DrugBank, as a potential inhibitor of the β-propeller domain of Keap1 (Keap1-DC). Chlorhexidine, an antimicrobial agent, is widely used as a mouthwash, skin cleanser, and intervening bacterial infection during childbirth. The biochemical assay confirmed a significant binding affinity of 30 µM and competitively inhibited the Nrf2 peptide interaction. Moreover, chlorhexidine also exerts cytoprotection in a neurotoxic cell model of PD through Keap1-Nrf2 disruption leading to nuclear translocation of Nrf2 and expression of downstream genes, HO-1, and NQO1. Hence, the chemical scaffold of chlorhexidine is a potential lead to develop new chemical libraries with drug-like properties for treating PD.

Communicated by Ramaswamy H. Sarma

Keywords:

• Pharmacophore
• Keap1
• β-propeller domain
• Nrf2 inhibitor
• chlorhexidine
• DrugBank
• repurposable

Acknowledgements

BP is grateful to the Department of Science & Technology (DST), Government of India (DST-FIST: SR/FST/LS-I/2017(C)), SERB-Department of Science and Technology (DST), Government of India (EMR/2015/00735), and ICMR, Government of India (BIC/12(19)/2012), for the financial support. SU is grateful to the Council of Scientific and Industrial Research (CSIR), Government of India, for the SRF fellowship (09/490(0103)/2019). PD is grateful to the Indian Council for Medical Research (ICMR), the Government of India, for the SRF fellowship (45/51/2018/PHA/BMS). GK is grateful to the Indian Council for Medical Research (ICMR), the Government of India, for the SRF fellowship (45/38/2019-BIO/BMS).

Authors’ contributions

BP designed the research; BP, SU, PD, and GK performed research and analyzed data; SB provided scientific inputs; BP, SU, and PD wrote the original draft; and all authors contributed to the final version of the manuscript.

Disclosure statement

The authors declare no competing interests.