Main Text
The unprecedented public health, economic, and social challenges
engendered by the current COVID-19 pandemic necessitate an urgent search
for effective clinical interventions to help reduce viral load and
epidemiological spread, improve prevention and control, and stem the
tide of rising morbidity and mortality (Spinelli & Pellino, 2020). Due
to the time lag of vaccine trials and de novo drug development
based on standard drug-target modeling, compound screens, and
multi-phase clinic testing, the most rapid and practical approach toward
new clinical options lies in drug repositioning of proven or promising
infectious control modalities (Li & De Clercq, 2020). For SARS-CoV-2,
the etiologic agent of COVID-19, this effort is significantly assisted
by previous endeavors to develop therapeutics for two prior smaller
epidemics, both caused by closely related coronavirus types. Severe
acute respiratory syndrome (SARS) and Middle Eastern Respiratory
Syndrome (MERS) each originated from outbreaks of betacoronaviruses with
significant sequence and structural similarity to the SARS-CoV-2
betacoronavirus (Zhu et al., 2020).
Dozens of clinical trials have thus far been launched since January
2020, at multiple sites, to assay for efficacy of various repurposed
drugs against SARS-CoV-2, most available on the National Library of
Medicine’s registry of clinical studies, others scraped from text-mining
of the available literature. Figure 1 summarizes current trials in
progress on the basis of the tested drugs, targets or mechanisms,
preliminary efficacy studies, current and prior literature on the drug’s
efficacy for betacoronavirus-related disease, and the specific
designating information for the relevant trials themselves including
their phase, scale, expected completion date, and other key descriptors.
This picture is rapidly changing as new efforts come online, but as of
April 17, 2020, at least 53 separate public clinical trials were either
in operation, completed with preliminary results, or in various stages
of planning. The tested modalities attempt a variety of approaches to
improve patient outcomes, some targeting the virus directly, others
seeking to counter its deleterious physiological sequelae through
immunomodulation or respiratory and circulatory support to reduce
mortality and morbidity.
Summary statistics for these early trials are provided in Figure 2. As
can be seen, drugs and targets linked to unique viral components and
processes—such as the viral protease and
RNA-dependent-RNA-polymerase—predominate in current trials. Several
drugs have demonstrated early promise in at least some preliminary
studies including lopinavir/ritonavir, remdesivir, and chloroquine or
hydroxychloroquine, and more than a third (for which comprehensive
descriptions were provided) are at or beyond Phase 3. Nevertheless, the
scale of most trials remains small, the vast majority are not
multi-centered, and evaluation of efficacy will take months or years to
carry out. Only a few clinical trials are enrolling greater than 1,000
participants, including the global WHO DISCOVERY trial, the
European-based INSERM trial, and the Adaptive COVID-19 Treatment Trial.
Moreover, the most commonly tested drugs have been drawn from antiviral
studies outside the prior body of research focusing on SARS and MERS.
Since the SARS and MERS outbreaks dissipated without approaching the
global impact of COVID-19, fledgling therapeutic studies for these
epidemics were generally not followed up, and animal and human data are
largely unavailable. However, a recent study noted significant in vitro
and in vivo activity of a known nucleoside analog with previous efficacy
against SARS and MERS, β-D-N4-hydroxycytidine (NHC), in reducing viral
load in cell culture and tissue damage in mice secondary to SARS-CoV-2
infection (Sheahan et al., 2020). NHC was one of nearly a dozen drugs to
have demonstrated potential in reducing the disease burden from SARS,
MERS, or both (De Clercq, 2006; Kumar, Jung, & Liang, 2013; Savarino,
2005), and the recent results support the notion that such repurposing
may be fruitful for COVID-19.
We have therefore systematically combed available literature, reports,
and commentaries to ascertain untested drugs with previous promise for
SARS and MERS that merit consideration for additional COVID-19 trials,
alongside the comprehensive clinical trial data elaborated previously.
We utilized an approach combining careful manual curation and
algorithmic scraping using a flexible Python language-based text-mining
tool, previously developed for research into prospective repurposable
drugs for Duchenne muscular dystrophy. Concomitantly, we systematically
examined the drugs with previous reported efficacy in the context of
SARS and MERS, then curated them on the basis of several factors most
indicative of potential in clinical trials to repurpose them for
SARS-CoV-2.
In assessing criteria to identify highly promising candidates for
COVID-19 drug repurposing, it has been noted that perhaps the primary
predictor of eventual failure in clinical trials is non-selectivity for
the target, contributing to unacceptable toxicity (Gayvert, Madhukar, &
Elemento, 2016). Therefore, in examining the as yet untested or
seldom-tested SARS and MERS drugs with potential for COVID-19
repositioning, particular weighting was given to those exhibiting a low
reported EC50 (or IC50) and high
Selectivity Index (SI) from cell culture studies. Attention was likewise
given to drugs which are not only selective for a viral target,
especially a component indispensable for viral replication, but also
substantially reduce viral load in vitro. Further consideration was
given for modalities demonstrating confirmation of potential efficacy
from multiple centers. With these factors as primary criteria for
identifying COVID-19 drug repurposing candidates, several especially
promising potential therapeutics were identified, summarized in Figure
3.
Of particular promise are a docking octapeptide, AVLQSGFR (Chou, Wei, &
Zhong, 2003; Gan et al., 2006), and a Phe-Phe dipeptide inhibitor, 18c
(Shie et al., 2005), with marked selectivity (> 1,000-fold)
for the betacoronaviral protease of SARS-CoV (3C-like protease, also
known as 3CL protease, 3CLpro, or Mpro) and demonstrated capacity to
reduce viral load in cell culture. Both agents exhibit not only
remarkable Selectivity Index (SI) values, but also low
IC50 and/or EC50 measurements that
suggest viability as practical drugs in vivo. As noted previously, the
viral protease is also the most frequent target of COVID-19 clinical
trials currently in progress or planning, but these candidates stand out
for their proven ability to selectively target 3CLpro and to bring about
a tangible reduction in viral infection capacity.
Encouraging results have also been observed for bananin (Huang, Zheng,
& Sun, 2008; Tanner et al., 2005; Wang et al., 2011), a viral helicase
inhibitor with > 30-fold selectivity in cell culture
studies; for calpain inhibitor VI (Barnard et al., 2004), with
> 100-fold selectivity; and for the herbal extract
hesperetin (Lin et al., 2005), with an SI > 300 and a
direct inhibitory effect on the 3CL protease. Bananin (Tanner et al.,
2005) and calpain inhibitor VI (Barnard et al., 2004) have likewise been
found to inhibit viral load and infection in vitro. Promising seminal
studies for inhibition of SARS or MERS infection have also emerged for
another protease inhibitor, cinanserin (Chen et al., 2005), and for
nafamostat (Yamamoto et al., 2016), a cellular serine protease inhibitor
that reduces viral spike protein priming. Alongside the recent findings
by Sheahan and coworkers with NHC, such results suggest that animal
studies and preliminary clinical trials with these agents, or closely
related chemical derivatives, may prove fruitful in expanding the
arsenal of drugs to combat the relentless spread, morbidity, and
mortality of COVID-19.