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Published on: January 19, 2024
Clofazimine: A Promising Inhibitor of Rabies Virus
Jiajing Wu1,2, Shouchun Cao3, Shan Lei1
1Department of HIV/AIDS and Sex-transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing, China.
Abstract:
With an almost 100% mortality rate, rabies virus (RABV) infection is a global concern. Limited post-exposure prophylaxis and lack of an effective treatment necessitate novel antiviral therapies against RABV. Here, using a high-throughput screening (HTS) method developed in our lab, 11 candidates with anti-RABV activity were identified from a library of 767 clinical drugs. Clofazimine (CFZ), an anti-leprosy drug, displayed an EC50 of 2.28 μM, and SI over 967 against RABV. Investigations into the underlying mechanisms revealed that CFZ targeted viral membrane fusion at the early stages of virus replication. Moreover, CFZ and Clofazimine salicylates (CFZS) exhibited elevated survival rates in vivo, compared with the positive control T-705. Thus, this study revealed CFZ as a promising drug against RABV infection.
Insights
Clofazimine, an anti-leprosy drug, shows potent antiviral activity against rabies virus (RABV) by inhibiting viral membrane fusion. This study identifies clofazimine as a promising therapeutic candidate for rabies infection.
Area of Science:
- Virology
- Infectious Diseases
- Drug Discovery
Background:
- Rabies virus (RABV) infection poses a significant global health threat with nearly 100% mortality.
- Existing post-exposure prophylaxis is limited, and effective treatments for rabies are lacking, necessitating new antiviral strategies.
Purpose of the Study:
- To identify novel antiviral drugs against RABV using a high-throughput screening (HTS) approach.
- To evaluate the efficacy and mechanism of action of promising drug candidates against RABV.
Main Methods:
- A library of 767 clinical drugs was screened using a laboratory-developed HTS method to identify compounds with anti-RABV activity.
- Mechanism of action studies were conducted to determine how identified compounds inhibit RABV replication.
- In vivo efficacy of lead compounds was assessed by comparing survival rates against a positive control.
Main Results:
- Eleven drug candidates with anti-RABV activity were identified from the screened library.
- Clofazimine (CFZ), an anti-leprosy medication, demonstrated significant antiviral activity with an EC50 of 2.28 μM and a selectivity index (SI) over 967.
- CFZ was found to inhibit viral membrane fusion during early stages of RABV replication.
- Both CFZ and Clofazimine salicylates (CFZS) improved survival rates in vivo compared to the positive control T-705.
Conclusions:
- Clofazimine (CFZ) is identified as a potent antiviral agent against RABV, targeting early viral replication steps.
- CFZ and its derivative CFZS show promising therapeutic potential for treating rabies infection, as evidenced by in vivo studies.
- This research highlights the potential of repurposed clinical drugs for developing novel rabies therapies.
