Screening of an FDA-Approved Compound Library Identifies Four Small-Molecule Inhibitors of Middle East Respiratory Syndrome Coronavirus Replication in Cell Culture
1st treatment shown to reduce risk in
March 2020 *, now known with p < 0.00000000001 from 422 studies, recognized in 42 countries.
|
CQ inhibits SARS-CoV, MERS-CoV, and HCoV-229E-GFP replication in the low-micromolar range.
30 preclinical studies support the efficacy of HCQ for COVID-19:
20 In Vitro studies Alsmadi, Andreani, Clementi, Dang, Delandre, Faísca, González-Paz, Kamga Kapchoup, Liu, Milan Bonotto, Mohd Abd Razak, Ou, Purwati, Shang, Sheaff, Wang, Wang (B), Wen, Yao, Yuan
de Wilde et al., 15 Jul 2014, peer-reviewed, 9 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
Abstract: Screening of an FDA-Approved Compound Library Identifies Four
Small-Molecule Inhibitors of Middle East Respiratory Syndrome
Coronavirus Replication in Cell Culture
Adriaan H. de Wilde,a Dirk Jochmans,b Clara C. Posthuma,a Jessika C. Zevenhoven-Dobbe,a Stefan van Nieuwkoop,c
Theo M. Bestebroer,c Bernadette G. van den Hoogen,c Johan Neyts,b Eric J. Snijdera
Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, Netherlandsa; Rega Institute for Medical Research, KU,
Leuven, Belgiumb; Department of Viroscience, Erasmus Medical Center, Rotterdam, Netherlandsc
I
n June 2012, a previously unknown coronavirus was isolated
from a patient who died from acute pneumonia and renal failure
in Saudi Arabia (1, 2). Since then, the virus, now known as the
Middle East respiratory syndrome coronavirus (MERS-CoV) (3),
has been contracted by hundreds of others in geographically distinct locations in the Middle East, and evidence for limited human-to-human transmission has accumulated (4). Travel-related
MERS-CoV infections were reported from a variety of countries in
Europe, Africa, Asia, and the United States, causing small local
infection clusters in several cases (http://www.who.int/csr/disease
/coronavirus_infections/en/). About 200 laboratory-confirmed
human MERS cases were registered during the first 2 years of this
outbreak, but recently, for reasons that are poorly understood
thus far, this number has more than tripled within just 2 months’
time (April-May 2014 [5]). This sharp increase in reported infections has enhanced concerns that we might be confronted with a
repeat of the 2003 severe acute respiratory syndrome (SARS) episode, concerns aggravated by the fact that the animal reservoir for
MERS-CoV remains to be identified with certainty (6–9). Furthermore, at about 30%, the current human case fatality rate is
alarmingly high, even though many deaths were associated with
underlying medical conditions. MERS-CoV infection in humans
can cause clinical symptoms resembling SARS, such as high fever
and acute pneumonia, although the two viruses were reported to
use different entry receptors, dipeptidyl peptidase 4 (DPP4) (10)
and angiotensin-converting enzyme 2 (ACE2) (11), respectively.
Coronaviruses are currently divided across four genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus (12). MERS-CoV was identified as a member of lineage C
August 2014 Volume 58 Number 8
of the genus Betacoronavirus (2), which also includes coronaviruses of bat (13, 14) and hedgehog (6) origin. Following the 2003
SARS epidemic, studies into the complex genome, proteome, and
replication cycle of coronaviruses were intensified. Coronaviruses
are enveloped viruses with a positive-sense RNA genome of unprecedented length (25 to 32 kb [12, 15, 16]). The crystal structures of a substantial number of viral nonstructural and structural
proteins were solved, and targeted drug design was performed for
some of those (reviewed in reference 17). Unfortunately, thus far,
none of these efforts resulted in antiviral drugs that were advanced
beyond the preclinical phase (18). The 2003 SARS-CoV epidemic
was controlled within a few months after its onset, and since then,
the virus has not reemerged, although close relatives continue to
circulate in bat species (14). Consequently, the interest in anticoronavirus drug development has been limited, until the emer-
Received 10 April 2014 Returned for..
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