SI: Advances in Antiviral Nucleoside Analogs and Their Prodrugs Antiviral Chemistry and Chemotherapy
Current and future use of nucleo(s)tide
prodrugs in the treatment of hepatitis C
Cyril B Dousson
This review describes the current state of discovery of past most important nucleoside and nucleotide prodrugs in the
treatment of hepatitis C virus infection as well as future potential drugs currently in discovery or clinical evaluation.
I highlight first generation landmark prodrug compounds which have been the foundations of incremental improvements
toward the discovery and approval milestone of Sofosbuvir. Sofosbuvir is the first nucleotide prodrug marketed for
hepatitis C virus treatment and the backbone of current combination therapies. Since this approval, new nucleotide
prodrugs using the same design of Sofosbuvir McGuigan prodrug have emerged, some of them progressing through
advanced clinical trials and may become available as new incremental alternative hepatitis C virus treatments in the
future. Although since Sofosbuvir success, only minimal design efforts have been invested in finding better liver targeted
prodrugs, a few novel prodrugs are being studied and their different modes of activation may prove beneficial over the
heart/liver targeting ratio to reduce potential drug–drug interaction in combination therapies and yield safer treatment
to patients. Prodrugs have long been avoided as much as possible in the past by development teams due to their
metabolism and kinetic characterization complexity, but with their current success in hepatitis C virus treatment, and
the knowledge gained in this endeavor, should become a first choice in future tissue targeting drug discovery programs
beyond the particular case of nucleos(t)ide analogs.
Hepatitis C virus, nucleoside analogs, nucleotide analogs, prodrugs, NS5B
Date received: 21 September 2017. accepted: 13 December 2017
According to a recent report,
in 2015 globally, an esti-
mated 71 million people were living with chronic
hepatitis C infection accounting for 1% of the world
population, with only 20% knowing their infection
status. Mortality was still increasing and an estimated
1.75 million new HCV infections occurred worldwide
in 2015. Infection with HCV becomes chronic in most
infected persons and a person may be infected with
HCV for as long as 30 years or more before developing
any clinical symptoms of disease and 20% or more
develop life-threatening end-stage chronic liver disease,
such as cirrhosis or hepatocellular carcinoma. In 2015,
HCV led to 411,000 deaths.
The research for more effective HCV treatments has
developed and advanced signiﬁcantly in the recent
years and the focus on direct-acting antiviral agents
(DAAs) and specially nucleotide prodrugs having a
broad genotypic coverage and high barrier to resistance
have emerged as the best promise for backbone com-
bination to eradicate HCV in the next decade.
Nucleo(s)tide prodrugs are pharmacologically inac-
tive modiﬁed analogs able to be transformed in vivo to
their parent nucleo(s)tide via metabolic or chemical
processes occurring in the body. For the purpose of
clarity, I will here use under the generic “prodrug”
term only “carrier prodrugs” (covalently bound chem-
ical entity releasing the “drug” by hydrolytic
cleavage at the target site) and not bioprecursors
Idenix, an MSD Company—Medicinal Chemistry Cap Gamma,
Cyril B Dousson, Idenix, an MSD Company—Medicinal Chemistry Cap
Gamma, 1682 rue de la Valsiere BP 50001, Montpellier 34189, France.
Antiviral Chemistry and Chemotherapy
2018, Vol. 26: 1–8
!The Author(s) 2018
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(chemical entity metabolized into the pharmacological-
ly active entity) as deﬁned elsewhere.
This review will cover the different main current and
future prodrugging strategies used with the more sig-
niﬁcant reported active nucleo(s)tides which landmark
the ﬁeld of HCV. Comprehensive reviews of nucleos(t)
ide prodrugs have been reported elsewhere.
Both nucleosides and nucleotides can be prodrugged
depending on the shortcoming properties one wants
Nucleoside prodrugging is performed on a nucleo-
side that can be efﬁciently metabolized to its active
triphosphate (TP) in order to overcome bioavailability
or tissue targeting shortcomings. The more common
oral bioavailability issues are usually due to lack of
•permeation through biological membranes (lipophi-
licity is too low) and the prodrug design will mask or
counterbalance the polar functions of the parent
nucleoside (e.g. isobutyryl esters of Balapiravir),
or taking advantage of amino acid active transport
(e.g. L-valine ester of Valopicitabine);
•solubility, which is less common with nucleoside
analogs, but can be mitigated by prodrugging with
polar or ionizable pro-moieties (e.g. valine esters);
Addressing tissue targeting topics can be more com-
plex as the required enzymatic pro-moiety cleavage in a
speciﬁc tissue can be different from one parent nucle-
oside analog to another as well as species dependent.
The ﬁrst nucleoside prodrug evaluated in clinical
trials for HCV was NM283 from Idenix (Figure 1), a
30-L-valine ester of its parent nucleoside NM107 setting
the scene in HCV therapies with the most used 20C-Me
sugar modiﬁcation. The valine ester substituent was
chosen to improve poor bioavailability of NM107
when given orally.
NM283 was shown in later clinical
phases to be not stable enough in the gastrointestinal
(GI) tract, leading to GI side effects and was
Other ﬁrst generation prodrugs followed with
Balapiravir and Mericitabine, both tri- and di-isobu-
tyryl esters, respectively, of their corresponding nucle-
oside (Figure 1).
None of these ﬁrst generation nucleoside prodrugs
led to sufﬁcient clinical beneﬁt to allow approval of a
simple nucleoside prodrug, because daily dose normal-
ized viral load reductions were too low (Table 1).
On the other hand, nucleotide prodrugging is usually
performed to overcome 50-monophosphorylation prob-
lem or to improve liver targeting. As opposed to nucle-
oside prodrugging, the advantage in HCV activity of a
50-monophosphate prodrug can be demonstrated in cell
culture experiments as shown in Table 2.
1. SATE-phosphoramidate prodrugs
The ﬁrst clinical proof of concept for such kind of
nucleotide prodrugs was reported by Idenix with the
discovery of IDX184 (Scheme 1).
prodrugs were then reported based on the 20C-Me well-
known sugar backbone with different prodrug moieties
giving various improvements over the parent
IDX184 is a benzylamine/“SATE” phosphorami-
date prodrug which beneﬁts from a thioester enzymatic
cleavage liberating the corresponding carboxylic acid
and the 2-thioethyl side chain which undergoes self
While ethylene sulﬁde was pro-
posed as a cleavage metabolite, it has been shown that
this metabolite was not found in vivo, but glutathione
adduct was instead formed.
The benzylamine phos-
phoramidic acid is further cleaved by a phosphorami-
dase to yield the 50-monophosphate.
metabolism by cellular kinases gives the active corre-
sponding TP (Scheme 1).
IDX184 improved dramatically the clinical dose efﬁ-
ciency as over a two weeks once a day 100 mg dose
Figure 1. First clinical stage nucleoside prodrugs. (a) Valopicitabine (NM283), (b) Balapiravir (R1626), and (c) Mericitabine (R7128).
2Antiviral Chemistry and Chemotherapy 0(0)
treatment, HCV viral load reduced by 2.7 log
one of the highest viral load reduction efﬁciency per
gram of drug at 27 (Table 1). However, IDX184 suf-
fered from dose-limited absorption as seen in the dose
escalation nonlinearity Cmax.
IDX184 clinical devel-
opment was stopped as a consequence of BMS-986094
severe cardiac side effects, both compounds sharing the
same active Nuc-TP in vivo (vide infra).
2. McGuigan prodrugs
GS-7977 (Sofosbuvir) is a McGuigan phosphorami-
date prodrug (L-alanine/phenol) originally developed
by Pharmasset and is to date the only nucleotide pro-
drug which has received approval for HCV treatment
in December 2013.
After the clinical proof of concept
of GS-7977, other groups have used similar McGuigan
prodrug as exempliﬁed by BMS-986094, AL-335,
ACH-3422, and MIV-802 to reduce the development
risk associated with the metabolites formed by the
pro-moieties (L-alanine and phenol). The cleavage
and release of these pro-moieties in vivo have been
well characterized for GS-7977 or other analogs bear-
ing the same prodrug stereochemistry.
The ﬁrst step involves hydrolysis of the carboxylic
ester by cathepsin A (Cat A) and carboxylesterase 1
followed by an intramolecular cyclization of the car-
boxylate on the phosphorus atom, displacing the phe-
nolate and followed by water hydrolysis of the unstable
cyclized intermediate to yield the alanyl phosphorami-
dic acid metabolite which is further hydrolyzed by the
enzyme hHint 1 to the nucleoside-monophosphate
(NMP). In the case of GS-7977, this NMP is then phos-
phorylated by UMP-CMP kinase to its nucleoside-
diphosphate (NDP), and ﬁnal phosphorylation
by Nucleoside DiPhosphate Kinase (NDPK) affords
its nucleoside-triphosphate (Scheme 2).
BMS-986094 is a McGuigan prodrug that was
designed to improve in vitro activity in the replicon
assay owing to an increase of the lipophilicity by
using a naphthol in place of the usual phenol, substitut-
ing the shorter isopropyl ester with a neopentyl and by
removing a hydrogen bond donor on the guanine base
with a 6 methoxy analog. These structural modiﬁca-
tions improved the replicon EC
with activities as
low as 10 nM but with a cytotoxic value CC
7mM giving a selectivity index (toxicity/activity) of
700 (Table 2).
BMS-986094 phase II clinical trial
was stopped due to a fatal cardiac adverse effect that
was characterized further as a mitochondrial toxicity
mainly due to its TP and to a lesser extent to its
Table 1. Clinical dose efficiency of HCV nucleoside and nucleotide prodrugs.
Prodrug Daily dose
Viral load reduction
) at end
viral load reduction
(Valopicitabine) 800 mg 1.2 (2 wk treatment) 1.5
(Balapiravir) 3000 mg
(1500 mg bid)
1.2 (2 wk treatment) 0.4
(Mericitabine) 3000 mg
(1500 mg bid)
2.7 (2 wk treatment) 0.9
100 mg 2.7 (2 wk treatment) 27.0
400 mg 4.7 (1 wk treatment) 11.8
100 mg 2.53 (1 wk treatment) 25.3
(Adafosbuvir) 800 mg 4.00 (1 wk treatment) 5.0
700 mg 3.4 (1 wk treatment) 4.9
300 mg 4.23 (1 wk treatment) 14.1
HCV: hepatitis C virus.
Genotype 1 patients.
Table 2. HCV activity in cell culture experiments.
7.600 0.3 >100 >13
1.100 1.2 >1 000 >909
0.850 0.7 >100 >118
0.203 16 >75 >370
0.092 >1087 >100 >1087
0.144 67 >100 >694
0.010 580 7 700
0.160 36 >100 >613
0.075 NR >100 >1333
0.050 NR >25 >500
0.045 >1111 >100 >2222
56.800 1 >100 >2
HCV: hepatitis C virus; NR: Not reported.
Genotype 1b replicon assay.
Fold change EC
prodrug activity (improvement of the
prodrug versus parent nucleoside).
The effect of neopentyl ester
prodrug of BMS-986094 in place of the isopropyl
ester present in Sofosbuvir can be clearly seen in a
previous study by McGuigan et al., where these
two esters were synthesized with the same nucleoside
backbone and tested.
The isopropyl ester analog
of BMS-986094 proved to be over 14 times less
toxic in the Huh7 cells, so some of the toxicity of
BMS-986094 can be attributed to its neopentyl
ester modiﬁcation. It has also been reported by
Deval et al., with another comparable pair of com-
pounds by making the BMS-986094-monophosphate
prodrug on Sofosbuvir nucleoside. The Sofosbuvir-
modiﬁed hybrid had an increase in the cell toxicity
assay of Huh7 and U937 cells compared to
(Rp and Sp isomer mixture)
otential structure from corres
references30, 31, 32
Figure 2. McGuigan phosphoramidate nucleotide prodrugs. (a) Sofosbuvir (GS-7977) (Sp isomer), (b) BMS-986094 (Rp and Sp
isomer mixture), (c) Adafosbuvir (AL-335) (Sp isomer), (d) ACH-3422*, and (e) MIV-802* (Sp isomer). *Potential structure from
Kalayanov et al.,
(Rp and Sp isomer mixture)
Scheme 1. SATE IDX184 nucleotide prodrug and its proposed decomposition pathway.
4Antiviral Chemistry and Chemotherapy 0(0)
Three other McGuigan prodrugs still in clinical
development are AL-335, ACH-3422, and MIV-802
for which little preclinical data have been reported but
for which the HCV replicon activity is similar or slightly
better than Sofosbuvir (Table 2). The early virologic
load decrease in patients is much less efﬁcient than
Sofosbuvir (Table 1) for the ﬁrst two more advanced
candidates (AL-335 and ACH-3422), and it was recently
announced that AL-335 would not be developed further
Although one cannot exclude that
MIV-802 or ACH-3422 could potentially progress fur-
ther in combination with other DAAs.
3. Cyclic phosphotriester (CPO) prodrugs
The 30,50-CPO prodrug structural unit shows possi-
ble signiﬁcant improvements on the medicinal chemis-
try perspective, allowing smaller molecular weight and
therefore better ligand efﬁciency as well as lower
number of rotational bonds which, with the former
property, may both provide enhanced passive diffusion
through cell membrane. Both GS-0938 and IDX19368
(Figure 3) are actually double prodrugs as they bear the
ethoxy masking group on the 6-guanine base position
allowing a better solubility of these guanosine deriva-
tives. The in vivo metabolism was studied in the case of
GS-0938 and is described in Scheme 3. It involves a ﬁrst
oxidative cleavage by cytochrome (CYP3A4), followed
by opening of the cyclic 30,50-phosphodiester (CPOH)
by phosphodiesterase, the last step being the hydrolysis
of the 6-ethoxy guanine prodrug by adenosine
deaminase-like protein 1.
4. D-amino acid based aryl-phosphoramidate prodrugs
IDX21437 is a D-amino acid phosphoramidate pro-
drug of the well-established HCV active 20-b-modiﬁed
ribonucleoside family. As seen in Table 2, it has a very
different proﬁle in cell culture experiments, compared
to other clinical candidates, due to the unnatural amino
acid conﬁguration part of its prodrug, giving a lack of
activity in the HCV replicon system and would there-
fore not be viewed by classical medicinal chemists as a
promising compound. But actually, this compound dis-
played an unexpectedly good in vivo proﬁle in regards
to its ability to form high levels of its corresponding
active TP in animal liver, the target organ for HCV.
The metabolism of IDX21437 was reported and proved
to require a different enzymatic system for the initial
cleavage compared to McGuigan prodrug Cat A
involvement (Scheme 4).
The different enzymes
involved in the metabolism of D-amino acid phosphor-
amidate is supposed to be responsible for the better
liver to heart selectivity, as D-alanylate phosphoramidic
acid metabolite was not observed in heart cells.
Currently, IDX21437 (now MK-3682) is progressing
in phase II combination studies.
5. Other miscellaneous prodrugs
Other HCV nucleotide prodrugs were reported in
early discovery studies as CC-1845 from Cocrystal,
for which the structure is unknown but likely
Figure 3. Clinical and preclinical 30,50-CPO prodrug.
(a) GS-0938 (Rp isomer) and (b) IDX19368 (Sp isomer).
NMP Alanylate phosphoramidic acid
Scheme 2. McGuigan prodrug metabolism.
a McGuigan prodrug of 20C-Me-2,6,-disubstituted
purine analog. However, recently the company has
declared that preclinical studies indicated higher than
acceptable toxicity and have now switched to a backup
From the ﬁrst nucleosides through the ﬁrst generation
of their prodrugs to the second generation of nucleo-
tide prodrugs demonstrating increasing added value of
liver targeting in HCV, no new simple nucleosides or
their prodrugs would be further developed but favoring
their nucleotide prodrugs as can be seen by the latest
candidates in discovery or ongoing clinical evaluation.
With the knowledge gathered by the different metabo-
lism pathways of pro-moieties, future nucleotide pro-
drugs will be designed toward more elaborated and
tissue targeted drugs with single or multiple prodrugs
and possible combinations of the above well character-
ized and main classes of prodrugs as can be already
seen in recent patent applications in the HCV and
other disease areas. I can envision for the future of
HCV nucleos(t)ide drugs better liver targeting based
on more speciﬁc liver metabolism, compared to other
tissues as exempliﬁed by IDX21437, rather than ﬁrst
path metabolism effect as observed in the earlier
per os prodrug design. HCV nucleotide drug discovery
has been a tremendous scientiﬁc emulation for the last
15 years and will be able to serve as a foundation case
4. D-aminoacid based Ar
Scheme 3. CPO prodrug metabolism.
(D-AA; Rp isomer) carboxylate
D-alanylate phosphoramidic acid
Scheme 4. D-amino acid phosphoramidate prodrug IDX21437 and its proposed metabolism.
6Antiviral Chemistry and Chemotherapy 0(0)
for other disease area nucleos(t)ide prodrug develop-
ment as well as, more broadly, prodrug targeting exam-
ple for other class of drugs in the future.
The author wishes to thank Dr Gilles Gosselin for his invalu-
able assistance in reviewing this manuscript.
Declaration of conflicting interests
The author is an employee of Idenix, an MSD company.
The author(s) received no ﬁnancial support for the research,
authorship, and/or publication of this article.
Cyril B Dousson http://orcid.org/0000-0002-6046-5032.
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