Antiviral activities of niclosamide and nitazoxanide against chikungunya virus entry and transmission

Abstract

Chikungunya disease results from an infection with the arbovirus, chikungunya virus (CHIKV). Symptoms of CHIKV include fever and persistent, severe arthritis. In recent years, several antiviral drugs have been evaluated in clinical trials; however, no registered antivirals have been approved for clinical therapy. In this study, we established a high-throughput screening (HTS) system based on CHIKV 26S mediated insect cell fusion inhibition assay. Our screening system was able to search potential anti-CHIKV drugs in vitro. Using this system, four compounds (niclosamide, nitazoxanide, niflumic acid, tolfenamic acid) were identified. These compounds were then further analyzed using a microneutralization assay. We determined that niclosamide and nitazoxanide exhibit ability to against CHIKV-induced CPE. The anti-CHIKV abilities of these compounds were further confirmed by RT-qPCR and IFA. Moreover, niclosamide and nitazoxanide were found to (1) limit virus entry, (2) inhibit both viral release and cell-to-cell transmission, and (3) possess broad anti-alphavius activities, including against two clinical CHIKV isolates and two alphaviruses: Sindbis virus (SINV) and Semliki forest virus (SFV). In conclusion, our findings suggested that niclosamide and nitazoxanide were able to inhibit CHIKV entry and transmission, which might provide a basis for the development of novel human drug therapies against CHIKV and other alphavirus infections.

Inhibition of rubella virus replication by the broad-spectrum drug nitazoxanide in cell culture and in a patient with a primary immune deficiency

“…We also demonstrated that NTZ suppresses multiple post-entry stages of RV infection as it was observed for other viruses (La Frazia et al, 2013;Shi et al, 2014;Wang et al, 2016). It was more effective at the early stages of the replication cycle and completely blocked RV infection at 10 μg/ml, the peak concentration of the drug (C max ) in human plasma after receiving a single 500-mg oral dose of NTZ (Broekhuysen et al, 2000); Alinia ® package insert.…”

Dual activity of niclosamide to suppress replication of integrated HIV-1 and Mycobacterium tuberculosis (Beijing)

“…This broad activity has led to its evaluation as a therapeutic agent for a number of cancers, including breast, colon, ovarian, prostate, and others [13][14][15][16]. It has also shown potential to treat bacterial and viral infections such as Bacillus anthracis [17], Pseudomonas aeruginosa [18] and Staphylococcus aureus [19], as well as SARS-CoV [20], Influenza [21], Chikungunya [22] and Zika [23] viruses. In addition to the above, niclosamide has been investigated as a potential anti-mycobacterial drug.…”

The medicinal chemistry of Chikungunya virus

“…Wang et al 76 shown CHIKV 26S mediated insect cell fusion assays could be used to search for anti-CHIKV drugs. From this platform, it was suggested the anti-alphaviruses properties of niclosamide (104) and nitazoxanide (105) also can affect CHIKV entry and transmission, which verified their potential use in human cells proved by U2OS cells (Table 6).…”

“…From this platform, it was suggested the anti-alphaviruses properties of niclosamide (104) and nitazoxanide (105) also can affect CHIKV entry and transmission, which verified their potential use in human cells proved by U2OS cells (Table 6). 76 2.2. Niclosamide and nitazoxanide can be promising compounds for the further development of anti-CHIKV drugs.…”