2015 A screen of the NIH Clinical Collection small molecule library identifies potential anti-coronavirus drugs

10 Pages·2015·1.62 MB·English

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A screen of the NIH Clinical Collection small molecule library identifies

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potential anti-coronavirus drugs

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Jianzhong Cao
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, J. Craig Forrest, Xuming Zhang ⇑

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Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States
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a r t i c l e
i n f o

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Article history:
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Received 1 July 2014
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Revised 8 October 2014
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Accepted 20 November 2014
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Available online xxxx

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Keywords
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:
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Coronavirus
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Small molecule
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NCC library
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Screening
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a b s t r a c t

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With the recent emergence of Middle East Respiratory Syndrome coronavirus in humans and the out-
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break of devastating porcine epidemic diarrhea coronavirus in swine, therapeutic intervention is urgently
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needed. However, anti-coronavirus drugs currently are not available. In an effort to assist rapid develop-
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ment of anti-coronavirus drugs, here we screened the NIH Clinical Collection in cell culture using a lucif-
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erase reporter-expressing recombinant murine coronavirus. Of the 727 compounds screened, 84 were
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found to have a significant anti-coronavirus effect. Further experiments revealed that 51 compounds
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blocked virus entry while 19 others inhibited viral replication. Additional validation studies with the
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top 3 inhibitors (hexachlorophene, nitazoxanide and homoharringtonine) demonstrated robust anti-
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coronavirus activities (a reduction of 6 to 8log10 in virus titer) with an IC50 ranging from 11 nM to
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1.2 lM. Furthermore, homoharringtonine and hexachlorophene exhibited broad antiviral activity against
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diverse species of human and animal coronaviruses. Since the NIH Clinical Collection consists of com-
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pounds that have already been through clinical trials, these small molecule inhibitors have a great poten-
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tial for rapid development as anti-coronavirus drugs.
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� 2014 Published by Elsevier B.V.
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1. Introduction

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Coronavirus is an enveloped RNA virus. It has a single-strand,

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positive-sense RNA genome that is associated with nucleocapsid

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(N) protein to form the nucleocapsid inside the envelope (Fan

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et al., 2005; Jayaram et al., 2006). The spike protein protrudes from

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the virion surface to confer viral infectivity and is the major deter-

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minant of species- and tissue-tropism. Coronaviruses can infect

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humans and diverse species of animals, causing respiratory, diges-

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tive, neurological and immune-mediated diseases. Most human

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coronaviruses cause mild respiratory illnesses such as common

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cold or enteric diseases such as diarrhea (Caul and Egglestone,

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1977; Resta et al., 1985; Zhang et al., 1994). But in 2003, a new

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coronavirus termed Severe Acute Respiratory Syndrome (SARS)-

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coronavirus suddenly emerged in the human population from wild

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animals (Drosten et al., 2003; Ksiazek et al., 2003; Marra et al.,

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2003; Rota et al., 2003), sickened more than 8000 people, and

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caused 774 deaths (CDC, 2004; Sorensen et al., 2006). Due to the

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fear caused by its ease of human-to-human transmission, disease

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severity and high mortality, the SARS outbreak posed a significant

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threat to public health and caused devastating economic loss. For-

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tunately, the epidemic subsided, and SARS has not re-emerged.

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However, another new coronavirus, termed Middle East Respira-

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tory Syndrome (MERS) coronavirus, recently emerged in the Mid-

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dle East and has now spread to dozens of countries (Lim et al.,

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2013; Mitka, 2013); it has infected more than 635 people and

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claimed 193 lives thus far (WHO, 2014). While the origins of SARS

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and MERS appear distinct, the respiratory disease similarities and

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high mortality rate has raised renewed concern about MERS’

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potential threat to public health on a global scale. Furthermore,

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although most of the existing animal coronaviruses are wide-

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spread, a new coronavirus strain, porcine epidemic diarrhea

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(PED) coronavirus, emerged several years ago in Asia and now

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has
spread
to
the
Americas,
including
the
United
States

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(Stevenson et al., 2013; Wang et al., 2014), causing significantly

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high mortality in affected piglets. This new epizootic disease has

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devastated the swine industry in these countries, having wiped

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out more than 10% of the U.S. pig population (De La Hamaide,

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2014). However, to date, there is no effective drug available for

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treatment of any coronavirus infection, although a few drugs have

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been
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tested in vitro (Al-Tawfiq et al., 2014; Barlough and Shacklett,

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1994; Falzarano et al., 2013; Morgenstern et al., 2005; Saijo et al.,

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2005).

http://dx.doi.org/10.1016/j.antiviral.2014.11.010
0166-3542/� 2014 Published by Elsevier B.V.

⇑ Corresponding author at: Department of Microbiology and Immunology,
University of Arkansas for Medical Sciences, 4301 W. Markham Street, Slot 511,
Little Rock, AR 72205, United States. Tel.: [phone]; fax: [phone]
5359.
E-mail address: