Chloroquine, a FDA-approved Drug, Prevents Zika Virus Infection and its Associated Congenital Microcephaly in Mice

Abstract

Zika virus (ZIKV) has become a global public health emergency due to its rapidly expanding range and its ability to cause severe congenital defects such as microcephaly. However, there are no FDA-approved therapies or vaccines against ZIKV infection. Through our screening of viral entry inhibitors, we found that chloroquine (CQ), a commonly used antimalarial and a FDA-approved drug that has also been repurposed against other pathogens, could significantly inhibit ZIKV infection in vitro, by blocking virus internalization. We also demonstrated that CQ attenuates ZIKV-associated morbidity and mortality in mice. Finally, we proved that CQ protects fetal mice from microcephaly caused by ZIKV infection. Our methodology of focusing on previously identified antivirals in screens for effectiveness against ZIKV proved to be a rapid and efficient means of discovering new ZIKV therapeutics. Selecting drugs that were previously FDA-approved, such as CQ, also improves the likelihood that they may more quickly reach stages of clinical testing and use by the public.

Bafilomycin A1 and U18666A Efficiently Impair ZIKV Infection

“…Our data show that bafilomycin A1 strongly impairs the entry of ZIKV Uganda 976 (known to cause only mild symptoms) and ZIKV French Polynesia PF13/251013-18 (associated with neurological complications) in A549 and in SH-SY5Y cells. These data are in line with previous observations describing that ammonium chloride and chloroquine have the potential to block ZIKV infection [38][39][40]. It also reflects the observations that the infection process of a variety of other flaviviruses, such as dengue virus or West Nile virus, can be inhibited by preventing the receptor-mediated endocytosis.…”

In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

“…Chloroquine is a widely used anti-malarial with immunomodulatory effects [1][2][3][4][5]. In a recent in vitro study chloroquine was found to inhibit the growth of SARS-CoV-2 in vitro [6].…”

Of chloroquine and COVID-19

“…The in vitro antiviral activity of chloroquine has been identified since the late 1960's (Inglot, 1969;Miller and Lenard, 1981;Shimizu et al, 1972) and the growth of many different viruses can be inhibited in cell culture by both chloroquine and hydroxychloroquine, including the SARS coronavirus (Keyaerts et al, 2004). Some evidence for activity in mice has been found for a variety of viruses, including human coronavirus OC43 (Keyaerts et al, 2009), enterovirus EV-A71 (Tan et al, 2018), Zika virus (Li et al, 2017) and influenza A H5N1 (Yan et al, 2013). However, chloroquine did not prevent influenza infection in a randomized, double-blind, placebo-controlled clinical trial (Paton et al, 2011), and had no effect on dengue-infecteds patient in a randomized controlled trial in Vietnam (Tricou et al, 2010).…”