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.
Highlights
Rabies is a viral disease that causes inflammation of the brain in humans and other mammals (Dharmalingam and Jothi, 2015)
Pseudovirus containing a firefly luciferase reporter gene enveloped by the Rabies virus (RABV) glycoprotein G was used for high-throughput screening (HTS) to select inhibitors of viral entry
HTS conditions including cell-seeding density and pseudotyped rabies virus (pRABV) dose were optimized as 50,000 cells/well and 1500 TCID50/well, respectively
Summary
Rabies is a viral disease that causes inflammation of the brain in humans and other mammals (Dharmalingam and Jothi, 2015). To prevent rabies virus from gaining access to the nervous system, the World Health Organization (WHO) recommends administering rabies immunoglobulin (RIG) along with four or five doses of rabies vaccine, especially in cases with severe exposure. Approximately 40,000–70,000 human die annually due to rabies worldwide, roughly 40% of which are children (Davis et al, 2015). The majority of these deaths occurred in Asia and Africa (Fooks et al, 2017). The main reasons are scarcity of RIG and failure to implement appropriate PEP (Jackson, 2013; World Health Organization, 2013)
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