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Antivirale in Nidovirus 2019
Antivirale in Nidovirus 2019
Arteriviruses
Virus-driven GFP
PRRSV CsA, Debio-064 expression, virus 5.1–5.2 µM (de Wilde et al., 2013a) –d – –
yields
Alphacoronaviruses
Increased cell
survival by
Virus-induced cell CsA
HCoV-OC43 CsA 2.5 µMc (Favreau et al., 2012) CypD interfering with
death treatment
virus-induced
apoptosis
CsA, ALV,
(Carbajo-Lozoya et al.,
NIM-811, other Inhibition of viru
HCoV-NL63 qPCR, virus yields0.8–6.6 µM 2014,Carbajo-Lozoya et al., CypA shRNA
CsA analogs, replication
2012,Pfefferle et al., 2011)
FK-506
(Carbajo-Lozoya et al.,
Virus-driven GFP 2012,de Wilde et al., Inhibition of viru
CsA, ALV, FK- or luciferase 2017a, de Wilde et al., shRNA, replication in
HCoV-229E 2.3–12.2 µM CypA?
506 expression, virus 2011,Pfefferle et al., knockout Huh7.5 cells, no
yields 2011, von Brunn et al., effect in Huh7
2015)
(Pfefferle et al.,
CypA,
a 2011,Tanaka et al., shRNA, Inhibition of viru
FCoV CsA, DTM Virus yields 2.7–4.1 µM CypB,
2015,Tanaka et al., knockout production
Pin1b
2012,Tanaka et al., 2017)
Betacoronaviruses
Virus-driven GFP
(de Wilde et al., 2017a, de
MHV CsA, ALV expression, virus 6.3–12 µM – – –
Wilde et al., 2011)
yields
(Carbajo-Lozoya et al.,
Virus-driven GFP
CsA, ALV, FK- 2012,de Wilde et al., CypA, siRNA,
SARS-CoV expression, virus 8.3–12 µM None
506 2017a, de Wilde et al., CypB shRNA
yields
2011,Pfefferle et al., 2011)
Gammacoronaviruses
IBV
CsA Virus yields 5.5 µM (Pfefferle et al., 2011) – – –
(Beaudette)
aDTM is an inhibitor of the parvulin Pin-1.
bPin-1 is member of the parvulin family and not a cyclophilin protein family member.
cOnly one inhibitor concentration used, no EC50 value was reported.
dNot reported.
Coronavirus infection in cell culture can also be inhibited by non-immunosuppressive CsA analogs, with EC 50 values similar to
those of CsA. Treatment with ALV led to a two- to five-log reduction of MERS-CoV, HCoV-229E, and SARS-
CoV progeny titers (EC50 values ranging from 1.3 to 8 µM) (de Wilde et al., 2017a). In addition, similar low-micromolar
concentrations of ALV, NIM-811, and other CsA analogs effectively blocked HCoV-NL63 infection (Carbajo-Lozoya et al.,
2014). Notably, for some CoVs variable antiviral effects were observed in different cell types, including Huh7 cells and
various Vero cell subtypes, with e.g. the antiviral effect of ALV against SARS-CoV being less pronounced in Vero-E6 cells than
in another Vero cell subclone (de Wilde et al., 2017a). The reasons for these variations in antiviral effects are poorly understood,
but may include variations in drug uptake, Cyp expression levels, and/or the overall kinetics of virus replication in a
particular cell line.
Unfortunately, ALV treatment did not protect mice from a challenge infection with mouse-adapted SARS-CoV, highlighting
that inhibition in cell culture infection models does not necessarily translate into an antiviral effect in vivo (de Wilde et al.,
2017a). This failure could be taken as a first sign that Cyp inhibitors may not be useful for the clinical treatment of CoV
infections. It is clear, however, that this conclusion first needs to be corroborated in further studies, also including other
compounds and other coronavirus (or nidovirus) models. This might more rigorously establish whether currently used Cyp
inhibitors are worth pursuing, either directly or as leads for the development of other host-directed antiviral drugs. Furthermore,
the development of non-immunosuppressive Cyp inhibitors with increased potency, solubility, or drug plasma levels may
enhance theantiviral activity in vivo. In any case, the use of Cyp inhibitors in fundamental research may still help to uncover the
putative role of Cyps in the replication of CoVs and other nidoviruses, as will be discussed below. Also, a summary of the
(putative) roles of Cyps in nidovirus replication is depicted in Fig. 1.