Improvement of the C-glycosylation Step for the Synthesis of Remdesivir

Article abstract of DOI:10.1021/acs.oprd.0c00310

The bulk supply of the antiviral C-nucleoside analogue remdesivir is largely hampered by a low-yielding C-glycosylation step in which the base is coupled to the pentose unit. Here, we disclose a significantly improved methodology for this critical transfo

Full text of DOI:10.1021/acs.oprd.0c00310

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Communication
Improvement of the C-glycosylation Step for the Synthesis of Remdesivir
Fei Xue, Xinbo Zhou, Ruijie Zhou, Xiaohan Zhou, Dian Xiao, Wu Zhong,
Eric Gu, Xiaowen Guo, Ji Xiang, Ke Wang, Likai Yang, and Yong Qin
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.0c00310 • Publication Date (Web): 05 Aug 2020
Downloaded from pubs.acs.org on August 5, 2020
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Improvement of the C-glycosylation Step for the
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Synthesis of Remdesivir
†,‣
‡,‣
†
†
‡
, ‡
§
Fei Xue, Xinbo Zhou, Ruijie Zhou, Xiaohan Zhou, Dian Xiao, Wu Zhong,* Eric Gu,
§
§
#
#
,†
Xiaowen Guo, Ji Xiang, Ke Wang, Likai Yang, Yong Qin*
AUTHOR ADDRESS
†
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and
Sichuan Province, and Sichuan Research Center for Drug Precision Industrial Technology, West
China School of Pharmacy, Sichuan University, Chengdu 610041, Sichuan Province, China.
‡ National Engineering Research Center for the Emergence Drugs, Beijing Institute of
Pharmacology and Toxicology, Beijing 100850, China.
§ Shanghai Syncores Technology Inc. Ltd., Shanghai 201203, China.
#
Chengdu Open Pharmaceutical Co., Ltd., Qionglai 611500, Sichuan Province, China.
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For Table of Contents Only
NH2
N
Si Si
Cl Cl
H
H
N
O
O
N
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i-Pr NH, n-BuLi
2
O
N
N
BnO
N
+
BnO
OH
OBn
N
BnO
OBn
THF, –78 ºC
Br
BnO
1
1
0.0 g scale: 74% (chromatography)
80.0 g scale: 62% (recrystallization)
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ABSTRACT: The bulk supply of the antiviral C-nucleoside analogue remdesivir is largely
hampered by a low-yielding C-glycosylation step in which the base is coupled to the pentose
unit. Here we disclose a significantly improved methodology for this critical transformation. By
utilizing diisopropylamine as a cost-effective additive, the addition reaction furnishes an optimal
yield of 75% of the desired ribofuranoside adduct, representing the highest yield obtained thus
far for this key step. The method proved suitable for hectogram scale synthesis without column
chromatographic operations.
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KEYWORDS: Diisopropylamine, C-glycosylation, Remdesivir, COVID-19
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INTRODUCTION
The global outbreak of Corona Virus Disease 2019 (COVID-19) caused by severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a severe threat to human health.1−5
Compared to its relatives (e.g., SARS-CoV and MERS-CoV), the new coronavirus exhibits a
more significant person-to-person transmission tendency. Most importantly, no drugs or vaccines
have thus far been approved to treat infections of SARS-CoV-2, which seems to render this
pandemic uncontrollable, with the number of infected cases worldwide exceeding ten million.
Under such circumstances, several existing antiviral drugs and drug candidates are actively
evaluated for their therapeutic potential for this disease.6,7,8 Among them, remdesivir (GS-5734,
1; Figure 1) represents one of the most promising compounds.8,9,10
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NH2
N
O
N
O
O
N
O
HN P O
CN
OH
Remdesivir
O
HO
Figure 1. Structure of remdesivir.
Remdesivir is an investigational small-molecule drug originally developed to treat Ebola
virus infections and later found to exhibit broad-spectrum activity against various RNA
viruses.11−17 In particular, a recent study (published on February 4 , 2020) clearly demonstrated
th
that remdesivir was effective against SARS-CoV-2 in vitro with an EC of 0.77 μM in Vero E6
5
0
1
7
cells. Of note, approximately one week prior to this report, Holshue et al disclosed that the first
COVID-19 patient in the USA had gradually recovered after receiving a compassionate
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administration of remdesivir. Subsequently, a number of clinical trials have been launched
worldwide to evaluate the efficacy and safety of remdesivir, 19 and other compassionate use of
2
0
this molecule has also been initiated, in the hope that it would benefit the treatment of the
epidemic COVID-19. Although the earliest clinical trials conducted in China did not yield
positive results in terms of reducing the death rate of severely affected patients due to
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insufficient data, preliminary data from a clinical trial led by the National Institute of Allergy
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and Infectious Diseases (NIAID) suggest a promising therapeutic effect of remdesivir. On May
1st 2020, the Food and Drug Administration (FDA) issued an Emergency Use Authorization
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2
(
EUA) for remdesivir to treat COVID-19 patients. Once further evidence supports the broad
clinical use of remdesivir, the bulk supply of the active pharmaceutical ingredients required for
the production of remdesivir would be an urgent concern.23
Structurally, remdesivir consists of three fragments: an adenine analogue (base), a pentose
unit, and a phosphoramidate side chain. A key challenge in the preparation of this C-nucleoside
analogue is the coupling of the ribose and base moieties. Previously, two-generation syntheses of
remdesivir, including three different methods for accessing ribofuranoside 4, have been
developed by chemists at Gilead Sciences (2 + 3 to 4; Figure 2).11,12,24-27 Temporary silyl
protection of the free primary amine group in the base fragment 2 was required in the addition
reaction between 2 and 3. Two silyl reagents (i.e., trimethylchlorosilane and 1,1,4,4-tetramethyl-
1
,4-dichloro disilethylene (5)) were employed to generate the corresponding protected
2
8
intermediates 6 and 7, respectively. In the first generation synthesis, subjection of bromide 2a
and ribolactone 3 to the conditions of TMSCl and n-BuLi at –78 º C furnished the desired C-
glycosylation product 4 in a low yield of 25% (method A; Figure 2).24,25 Alternatively, the use of
disilane 5 and NaH in this transformation could deliver 4 in a reported yield of 60% on 4.4 g
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scale (method B; Figure 2).12,26,27 The authors of the original studies added that “the efficiency of
both conditions (in the first generation synthesis) was suboptimal as the yields were capricious
and highly dependent on the cryogenic temperatures and the rate of n-BuLi addition required for
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the transformation”. In the second generation synthesis (method C; Figure 3), iodide 2b was
employed as the source of the base unit, with a combination of TMSCl, PhMgCl, and i-
PrMgCl·LiCl reagents, which resulted in a 40% yield of 4.11,25,26 We attempted to reproduce
these documented procedures on a decagram scale11,25,26 which resulted in the isolation of 4 with
yields in the range of 21–42% (see Table S1 in the Supporting Information). Evidently, none of
the three above approaches efficiently addressed this problematic synthetic step, and the
aforementioned techniques are not suitable for scale-up preparation of remdesivir. Until very
recently, during the course of our manuscript preparation, the Gilead scientists reported an
optimization of method C for the critical C-glycosylation step, in which NdCl and n-Bu NCl
3
4
were employed to facilitate the addition of lactone 3 with TMS-protected amine 2b (Method D;
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Figure 2). The 282 kg scale-up synthesis of compound 4 with 69% yield proved the reliability
of this method. In this report, we describe an alternative improvement for the C-glycosylation
step, which renders the synthesis of remdesivir simple and efficient, with the aim of meeting the
demand for its large-scale synthesis.
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the 1st generation synthesis
method A24,25: 25% yield
a, TMSCl, THF, rt;
method B26,27: 60% yield
NH2
N
NH2
N
2
2a, 5, NaH, THF, rt;
n-BuLi, 3, –78 ºC
n-BuLi, , –78 ºC
3
N
N
the 2nd generation synthesis
method C11,12: 40% yield
O
N
N
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BnO
X
method D : 69% yield
2b, TMSCl, PhMgCl,
i-PrMgCl, THF, –20 ºC;
OH
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a X = Br
2b X = I
2b, TMSCl, THF, rt; PhMgCl,
BnO
OBn
4
i-PrMgCl•LiCl, 0 ºC; 3, –20 ºC
3
, NdCl , n-Bu NCl, THF, –20 ºC
3
4
TMS
TMS
N
Si Si
N
N
N
O
O
BnO
Si Si
N
BnO
OBn
Cl Cl
N
N
N
3
5
X
6
X
7
Figure 2. Reported methods for accessing a key intermediate (4) in the remdesivir synthesis.
RESULTS AND DISCUSSION
Efficient protection of the free amine group in 2 would be essential for the successful
addition reaction of base 2 to lactone 3. We envisioned that the addition of a secondary amine
might be helpful for improving the reaction efficiency (Figure 3). First, the secondary amine
could serve to activate disilane 5 through the formation of a disilyl substituted cyclic quaternary
30
amine salt 8, thereby promoting the exchange of the silyl groups between the inactive primary
amine in 2 and the secondary amine to form cyclic disilazane 7. Second, a stablized lithium
intermediate 9 could be formed in the presence of the secondary amine after lithium-halogen
exchange with 7, which would subsequently facilitate the addition of the base motif to lactone 3
to yield the desired ribofuranoside 4.
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NH2
NH2
N
O
O
BnO
Si Si
Cl Cl
N
5
3
BnO
R NH, n-BuLi
OBn
N
N
O
N
N
X
BnO
OH
2
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BnO
OBn
X = Br or I
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R NLi
2
n-BuLi
Si Si
N
exchange
Cl
R
R
8
+ 3
Si Si
N
Si Si
N
R NH, n-BuLi
2
N
N
N
N
N
N
Li
Li
N
X
9
7
R
R
Figure 3. Working hypothesis for an improved synthesis of 4.
With the above working hypothesis in mind, we initiated our studies by performing the
reactions with bromide 2a (1.0 gram scale) and lactone 3 employing disilane 5 in the presence of
n-BuLi with various secondary amines (Table 1). When secondary amines bearing two linear
alkyl groups (such as diethylamine, dipropylamine, and dibutylamine) were used, the addition
reactions proceeded to afford 4 in moderate yields (41–54%, entries 1–3). To our delight, bulkier
alkyl substituents in the secondary amine were beneficial for improving the reaction efficiency.
As a result, conducting the reaction in the presence of diisopropylamine led to the generation of
4
in 74% yield (entry 4). Notably, similar results were obtained with other bulky secondary
amines: diisobutylamine (71%, entry 5), dicyclohexylamine (70%, entry 6), and 2,2,6,6-
tetramethylpiperidine (74%, entry 7). For the purposes of comparison, the use of tertiary amines
was likewise evaluated. For instance, we performed the addition reaction of 2a and 3 under the
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identical conditions of entry 4, except for the replacement of diisopropylamine with
diisopropylethylamine, which resulted in a lower yield (49%, entry 8) of product 4.
Table 1. Effect of Organic Amines in the Addition Reactiona
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NH2
O
NH2
N
O
BnO
N
Si Si
Cl Cl
5
3
N
BnO
OBn
N
O
N
N
BnO
OH
OBn
Br
2
a
R NH, n-BuLi, THF, –78 ºC, 2 h
4
2
BnO
[
1.0 gram scale]
Entry
1
R NH
Yield (%)
41
Entry
5
R NH
Yield (%)
71
2
2
H
N
H
N
H
N
H
N
2
3
45
54
6
7
70
74
H
N
N
H
H
N
4
74
8
N
49
a
Reactions were conducted on 1.0 gram scale of 2a with 1.1 equiv. of 5, 1.1 equiv. of R NH, 4.3
2
equiv. of n-BuLi, and 2.0 equiv. of 3 at 0.08 mol/L concentration unless otherwise stated. Yields
were determined according to the isolated materials through column chromatography.
Based on the above preliminary results, we then carried out scale-up experiments
employing diisopropylamine as an additive (Table 2). A 10 g-scale addition of 2a to lactone 3
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was performed according to the conditions described in Table 1, leading to the generation of
adduct 4 in 75% yield (entry 1). To further improve the practicality of the addition process, we
sought to reduce the amount of solvent and increase the reaction concentration. Specifically, a
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4% yield was observed when conducting the reaction at the concentration of 0.20 mol/L (entry
), comparable to that of 0.08 mol/L (entry 1), while the reaction at 0.25 mol/L led to a slightly
diminished yield (70%, entry 3). Moreover, effect of the equivalents of lactone 3 was
investigated. Lowering the loading of 3 delivered inferior results (i.e., 1.8 equiv., 62%, entry 4;
1
.6 equiv., 59%, entry 5) compared to that obtained with 2.0 equiv. of 3. With the optimized
reaction conditions (entry 2), a 180 g-scale experiment was conducted, which occurred smoothly
to provide 4 with 62% yield and 99.3% purity after recrystallization without the need of column
chromatographic operations (entry 6).
Table 2. Further optimization studies and scale-up synthesisa
NH2
N
O
NH2
N
O
BnO
Si Si
Cl Cl
5
3
BnO
OBn
N
N
N
O
N
Br
BnO
OH
OBn
i-Pr NH, n-BuLi, THF, –78 ºC, 2 h
2
2a
4
BnO
Entry
Scale of 2a
Equiv. of 3
Concentration (mol/L)
Yield (%)
1
2
3
10.0 g
10.0 g
10.0 g
2.0
2.0
2.0
0.08
0.20
0.25
75b
74b
70b
1
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62b
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10.0 g
10.0 g
180.0 g
1.8
1.6
2.0
0.20
0.20
0.20
59b
62c
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a
Reactions were conducted with 1.1 equiv. of 5, 1.1 equiv. of i-Pr NH, and 4.3 equiv. of n-BuLi
2
b
unless otherwise stated. Yields were calculated based on the materials isolated through column
c
chromatography. The yield was obtained after recrystallization.
CONCLUSION
In summary, the crucial C-glycosylation step that ordinarily limits the overall efficiency of
remdesivir synthesis has been significantly improved by the use of a cost-effective secondary
amine, diisopropylamine. Thus, subjecting the base unit 2a and ribolactone 3 to the optimal
reaction conditions delivered up to 75% yield of the anticipated ribofuranoside 4, which, to the
best of our knowledge, represents the highest yield obtained for this critical transformation thus
far. Furthermore, the procedure is amenable to hectogram scale synthesis without column
chromatographic operations, and as such would be highly advantageous for the large-scale
manufacture of the antiviral, remdesivir.
EXPERIMENTAL DETAILS
General Information. All reagents were purchased from commercial suppliers and were used
without further purification. The product of the decagram scale synthesis was purified by flash
column chromatography on silica gel (200 – 300 meshes) from the Anhui Liangchen Silicon
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Material Company in China. H NMR and C NMR spectra were recorded on Varian INOVA-
400/54, Agilent DD2-600/54 and calibrated by using deuterated dimethyl sulfoxide (DMSO-d6,
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H NMR: δ = 2.50, C NMR: δ = 39.5) unless otherwise noted. High-resolution mass spectra
(HRMS) were recorded on Agilent LC-MSD TOF ESI mass spectrometers.
General Procedure for Synthesis of Compound 4 by Using Different Amines. To an oven-
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dried round-bottom flask equipped with a stir bar was added 7-bromopyrrolo[2,1-f][1,2,4]triazin-
-amine (2a, 1.00 g, 4.694 mmol, 1.0 equiv.). The flask was evacuated and backfilled with argon
4
for three times. Under the protection of argon, anhydrous THF (40 mL) was added and the
mixture was stirred at room temperature for 5 min before a solution of 1,2-
bis(chlorodimethylsilyl) ethane (5, 1.111 g, 5.163 mmol, 1.1 equiv.) in anhydrous
tetrahydrofuran (5 mL) was added. The resulting mixture was stirred for 10 min. Then amine
(5.163 mmol, 1.1 equiv.) was added. After stirring at room temperature for 5 min, the resulting
mixture was cooled to ‒78 °C over 20 min. At this point, n-BuLi (2.5 M in n-hexane, 8.1 mL,
2
0.18 mmol, 4.3 equiv.) was added dropwise over 30 min through a syringe to the mixture and
the reaction was allowed to stir at ‒78 °C for additional 15 min. Next, a solution of lactone 3
3.930 g, 9.388 mmol, 2.0 equiv.) in anhydrous THF (5 mL) was added dropwise over 10 min
(
under the argon atmosphere through a syringe. After the reaction was stirred at ‒78 °C for 2 h, it
was allowed to warm slowly to 0 to 10 °C. The reaction was quenched by adding 1 M citric acid
(50 mL) and stirred vigorously for 15 min. Then the layers were separated and the aqueous layer
was extracted with EtOAc (3 × 30 mL). The organic layers were combined and washed
sequentially with water (1 × 50 mL), saturated aqueous NaHCO (1 × 50 mL) and brine (1 × 50
3
mL). The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated
under reduced pressure. The residue was subjected to silica gel column chromatography (50%
EtOAc in petroleum ether to 100% EtOAc to 10% MeOH in EtOAc) to give 4 as white foam.
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Decagram Scale Synthesis of Compound 4 Under the Optimized Reaction Conditions. An
oven-dried three-neck round-bottom flask equipped with a stir bar and an additional funnel was
charged with 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (2a, 10.0 g, 46.94 mmol, 1.0 equiv.).
The above flask was evacuated and backfilled with argon for three times. Under the protection of
argon, anhydrous THF (80 mL) was added and the mixture was stirred at room temperature for 5
min before a solution of 1,2-bis(chlorodimethylsilyl) ethane (5, 11.1 g, 51.63 mmol, 1.1 equiv.)
in anhydrous tetrahydrofuran (20 mL) was added. The resulting mixture was stirred for 10 min.
Then diisopropylamine (7.3 mL, 51.63 mmol, 1.1 equiv.) was added. After stirring at room
temperature for 5 min, the resulting mixture was cooled to ‒78 °C over 20 min. At this point, n-
BuLi (2.5 M in n-hexane, 81 mL, 201.8 mmol, 4.3 equiv.) was added dropwise over 45 min
through the additional funnel to the mixture. Note: the dropwise addition of n-BuLi is essential
for this exothermic step. The addition time depends on the volume of n-BuLi, during which the
reaction temperature should be kept below ‒78 °C. In the decagram scale case, a 45 min period
could guarantee the complete formation of lithium intermediate. After the additional funnel was
rinsed by anhydrous THF, a solution of lactone 3 (39.3 g, 93.88 mmol, 2.0 equiv.) in anhydrous
THF (50 mL) was added dropwise over 20 min under the argon atmosphere, and the reaction was
allowed to stir at ‒78 °C for 2 h. Then the cold bath was removed and the mixture was slowly
warmed to 0 to 10 °C. The reaction was quenched by adding 1 M citric acid (200 mL) and stirred
vigorously for 15 min. Then the layers were separated and the aqueous layer was extracted with
EtOAc (3 × 200 mL). The organic layers were combined and washed sequentially with water (1
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×
250 mL), saturated aqueous NaHCO (1 × 250 mL) and brine (1 × 250 mL). The organic phase
3
was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.
The residue was subjected to silica gel column chromatography (50% EtOAc in petroleum ether
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to 100% EtOAc to 10% MeOH in EtOAc ) to give the mixture of isomers 4 (19.2 g, 74%) as
white foam. The analytical data were consistent with data previously reported in the literature.11
1
H-NMR (400 MHz, DMSO-d ): δ 8.10 (br s, 2H), 8.02 (s,1H), 7.37 – 7.23 (m, 11H), 7.17 –
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.12 (m, 3H), 7.03 – 7.01 (m, 2H), 6.98 (d, J = 4.0 Hz, 1H), 5.41 (d, J = 4.0 Hz, 1H), 5.10 (d, J =
.0 Hz, 1H), 4.61 – 4.56 (m, 2H), 4.54 – 4.47 (m, 4H), 4.08 – 3.99 (m, 1H), 3.98 – 3.95 (m, 1H),
1
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.71 (dd, J = 8.0, 4.0 Hz, 1H), 3.50 (dd, J = 8.0, 4.0 Hz, 1H); C-NMR (100 MHz, DMSO-d ):
6
δ 187.97, 155.86, 148.98, 138.63, 138.45, 138.42, 138.15, 128.63, 128.25, 128.22, 128.16,
1
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28.15, 127.83, 127.77, 127.73, 127.64, 127.61, 127.55, 127.49, 127.46, 127.42, 127.28, 127.22,
27.11, 127.04, 118.57, 117.52, 103.12, 102.27, 81.89, 80.85, 72.48, 72.31, 71.70, 71.40, 69.37;
+
HRMS (ESI): m/z calcd. for C H N NaO [M + Na] 575.2265; found 575.2260.
3
2
32
4
5
Hectogram Scale Synthesis of Compound 4 Under the Optimized Reaction Conditions.
An oven-dried 20 L reactor was charged with 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (2a,
180.0 g, 0.845 mol, 1.0 equiv.) and anhydrous THF (1.44 L) under an atmosphere of nitrogen at
2
0 °C. The mixture was stirred for 10 min before a solution of 1,2-bis(chlorodimethylsilyl)
ethane (5, 200.0 g, 0.929 mol, 1.1 equiv.) in anhydrous tetrahydrofuran (360 mL) was added at
the same temperature. The resulting mixture was stirred for 15 min. Then diisopropylamine (94.1
g, 131 mL, 0.929 mol, 1.1 equiv.) was added. After stirring for 10 min, the reaction was cooled
to ‒85 to ‒78 °C. At this point, n-BuLi (4, 2.5 M in n-hexane, 1.45 L, 3.634 mol, 4.3 equiv.) was
added dropwise over 4 h while maintaining the reaction temperature below ‒78 °C during the
exothermic addition, and the resulting mixture was allowed to stir at ‒85 to ‒78 °C for 30 min.
Next, a solution of lactone 3 (707.2 g, 1.69 mol, 2.0 equiv.) in anhydrous THF (900 mL) was
added dropwise over 3 h while maintaining the temperature between ‒85 to ‒78 °C. After the
reaction was stirred at the same temperature for another 2 h, it was allowed to warm slowly to 0
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to 10 °C. The reaction was quenched by the addition of 1 M citric acid (3.6 L) and the
temperature was maintained below 25 °C while vigorously stirring for 10 min. Then the layers
were separated and the aqueous layer was extracted with EtOAc (3 × 3.6 L). The organic layers
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were combined and washed sequentially with water (1 × 3.6 L), saturated aqueous NaHCO (1 ×
3
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.6 L) and brine (1 × 3.6 L). The organic phase was then concentrated in vacuo at 30 °C to
remove the majority of organic solvents. The residual solvents were removed by adding tert-
butyl methyl ether (3.6 L) and evaporated at 30 °C under reduced pressure. The mixture was
finally concentrated in vacuo to a total batch volume of 540 mL, whereupon n-heptane (3600
mL) was added. The resulting mixture was heated to 50 °C and stirred at this temperature for 30
min. Then it was allowed to cool to 0 °C. The resulting pale yellow solid was collected by
filtration. The filter cake was rinsed with n-heptane (540 mL) and dried under vacuum at 30 °C
to afford pale yellow solid of product 4 (291.5 g, 62%). Purity: 99.3% (Flow rate: 1.0 mL/min;
Column: Waters XTERRA MS C18 Column, 4.6 × 150 mm, 3.5 μm; Temperature: 45 °C;
Mobile phase A: water with 0.1% (v/v) trifluoroacetic acid; Mobile phase B: acetonitrile with
0
.1% (v/v) trifluoroacetic acid; Gradient elution: mobile phase A/B = 95:5 (0-5 min) to mobile
phase A/B = 5:95 (5-32 min) to mobile phase A/B = 95:5 (32-40 min), t = 19.272 min).
R
ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge at DOI:
NMR spectra of compounds; (PDF)
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AUTHOR INFORMATION
Corresponding Authors
Wu Zhong － National Engineering Research Center for the Emergence Drugs, Beijing
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Institute of Pharmacology and Toxicology, Beijing 100850, China;
Email: zhongwu@bmi.ac.cn
Yong Qin － Key Laboratory of Drug-Targeting and Drug Delivery System of the Education
Ministry and Sichuan Province, and Sichuan Research Center for Drug Precision Industrial
Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041,
Sichuan Province, China;
Email: yongqin@scu.edu.cn
Authors
Fei Xue － Key Laboratory of Drug-Targeting and Drug Delivery System of the Education
Ministry and Sichuan Province, and Sichuan Research Center for Drug Precision Industrial
Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041,
Sichuan Province, China
Xinbo Zhou － National Engineering Research Center for the Emergence Drugs, Beijing
Institute of Pharmacology and Toxicology, Beijing 100850, China
Ruijie Zhou － Key Laboratory of Drug-Targeting and Drug Delivery System of the
Education Ministry and Sichuan Province, and Sichuan Research Center for Drug
Precision Industrial Technology, West China School of Pharmacy, Sichuan University,
Chengdu 610041, Sichuan Province, China
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Xiaohan Zhou － Key Laboratory of Drug-Targeting and Drug Delivery System of the
Education Ministry and Sichuan Province, and Sichuan Research Center for Drug
Precision Industrial Technology, West China School of Pharmacy, Sichuan University,
Chengdu 610041, Sichuan Province, China
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Dian Xiao － National Engineering Research Center for the Emergence Drugs, Beijing
Institute of Pharmacology and Toxicology, Beijing 100850, China
Xiaowen Guo － Shanghai Syncores Technology Inc. Ltd., Shanghai 201203, China
Ji Xiang － Shanghai Syncores Technology Inc. Ltd., Shanghai 201203, China
Ke Wang － Chengdu Open Pharmaceutical Co., Ltd., Qionglai 611500, Sichuan Province,
China
Likai Yang － Chengdu Open Pharmaceutical Co., Ltd., Qionglai 611500, Sichuan Province,
China
Author Contributions
These authors contributed equally.
‣
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Wu Zhong thanks National Science and Technology Major Projects for “Major New Drugs
Innovation and Development” (2018ZX09711003), Yong Qin thanks financial support from
National Natural Science Foundation of China (21921002 and 21991114) and Special Funds for
Prevention and Control of COVID-19 of Sichuan University, and Likai Yang thanks Chengdu
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Municipal Science and Technology Bureau (2020-YF08-00002-GX). We are grateful to Prof.
Chunming Cui (Nankai University) for helpful discussions.
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and GS-441524 as therapeutic options for coronaviruses. One Health 2020, 9, 100128.
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734 against Ebola virus in rhesus monkeys. Nature 2016, 531, 381‒385.
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(
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