Isosorbide-based peptidomimetics as inhibitors of hepatitis C virus serine protease

Article abstract of DOI:10.1016/j.bmcl.2017.07.027

Hepatitis C infection is a cause of chronic liver diseases such as cirrhosis and carcinoma. The current therapy for hepatitis C has limited efficacy and low tolerance. The HCV encodes a serine protease which is critical for viral replication, and few protease inhibitors are currently on the market. In this paper, we describe the synthesis and screening of novel isosorbide-based peptidomimetic inhibitors, in which the compounds 1d, 1e, and 1i showed significant inhibition of the protease activity in vitro at 100?μM. The compound 1e also showed dose-response (IC₅₀?=?36?±?3?μM) and inhibited the protease mutants D168A and V170A at 100?μM, indicating it as a promising inhibitor of the HCV NS3/4A protease. Our molecular modeling studies suggest that the activity of 1e is associated with a change in the interactions of S2 and S4 subsites, since that the increased flexibility favors a decrease in activity against D168A, whereas the appearance of a hydrophobic cavity in the S4 subsite increase the inhibition against V170A strain.

Full text of DOI:10.1016/j.bmcl.2017.07.027

Accepted Manuscript
Isosorbide-based peptidomimetics as inhibitors of Hepatitis C virus serine pro-
tease
Aline C. Portela, Thalita G. Barros, Camilo H. da S. Lima, Luiza R.S. Dias,
Pedro H.R. de A. Azevedo, Anna Sophia C.L. Dantas, Ronaldo Mohana-Borges,
Gustavo T. Ventura, Sergio Pinheiro, Estela M.F. Muri
PII:
S0960-894X(17)30716-3
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.07.027
BMCL 25140
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
30 March 2017
4 July 2017
6 July 2017
Please cite this article as: Portela, A.C., Barros, T.G., da S. Lima, C.H., Dias, L.R.S., de A. Azevedo, P.H.R., Dantas,
A.S.C.L., Mohana-Borges, R., Ventura, G.T., Pinheiro, S., Muri, E.M.F., Isosorbide-based peptidomimetics as
inhibitors of Hepatitis C virus serine protease, Bioorganic & Medicinal Chemistry Letters (2017), doi: http://
dx.doi.org/10.1016/j.bmcl.2017.07.027
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Graphical Abstract
Isosorbide-based peptidomimetics as
inhibitors of Hepatitis C virus serine
protease
Leave this area blank for abstract info.
Aline C. Portelaa, Thalita G. Barrosa, Camilo H. da S. Limaa, Luiza R. S. Diasa, Pedro H. R. de A. Azevedoa,
Anna Sophia C. L. Dantasa, Ronaldo Mohana-Borgesb, Gustavo T. Venturac, Sergio Pinheirod, Estela M. F.
Muria,
a Laboratório de Química Medicinal, Departamento de Tecnologia Farmacêutica, Faculdade de Farmácia,
Universidade Federal Fluminense, Rua Mario Viana 523, Santa Rosa, 24241-000, Niterói, RJ, Brazil.
b Laboratório de Genômica Estrutural, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio
de Janeiro, Rio de Janeiro, RJ, Brazil.
c Laboratório de Glicobiologia Estrutural e Funcional, Instituto de Biofísica Carlos Chagas Filho,
Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
d
Departamento de Química Orgânica, Instituto de Química, Universidade Federal Fluminense, Niterói, RJ,
Brazil.

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Isosorbide-based peptidomimetics as inhibitors of Hepatitis C virus serine
protease
Aline C. Portelaa, Thalita G. Barrosa, Camilo H. da S. Limaa, Luiza R. S. Diasa, Pedro H. R. de A.
Azevedoa, Anna Sophia C. L. Dantas a, Ronaldo Mohana-Borgesb, Gustavo T. Venturac, Sergio Pinheirod,
Estela M. F. Muria,
a Laboratório de Química Medicinal, Departamento de Tecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal Fluminense, Rua Mario Viana
523, Santa Rosa, 24241-000, Niterói, RJ, Brazil.
b Laboratório de Genômica Estrutural, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
c Laboratório de Glicobiologia Estrutural e Funcional, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ,
Brazil.
d Departamento de Química Orgânica, Instituto de Química, Universidade Federal Fluminense, Niterói, RJ, Brazil.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Hepatitis C infection is a cause of chronic liver diseases such as cirrhosis and carcinoma. The
current therapy for hepatitis C has limited efficacy and low tolerance. The HCV encodes a serine
protease which is critical for viral replication, and few protease inhibitors are currently on the
market. In this paper, we describe the synthesis and screening of novel isosorbide-based
peptidomimetic inhibitors, in which the compounds 1d, 1e, and 1i showed significant inhibition
Available online
of the protease activity in vitro at 100 µM. The compound 1e also showed dose-response (IC50
=
Keywords:
Peptidomimetics
Isosorbide
36 ± 3 µM) and inhibited the protease mutants D168A and V170A at 100 µM, indicating it as a
promising inhibitor of the HCV NS3/4A protease. Our molecular modeling studies suggest that
the activity of 1e is associated with a change in the interactions of S2 and S4 subsites, since that
the increased flexibility favors a decrease in activity against D168A, whereas the appearance of
a hydrophobic cavity in the S4 subsite increase the inhibition against V170A strain.
HCV
Serine proteases
Molecular docking
Molecular dynamic simulation
MMPBSA
2017 Elsevier Ltd. All rights reserved.
5
Hepatitis C virus (HCV) infection is a global health problem
with over 170 million people infected worldwide. Chronic HCV
infection is associated with liver cirrhosis and hepatocellular
carcinoma, being HCV the primary cause of liver transplantation
around the world. 1
SER139 involved in the catalytic triad of the HCV protease. In
2014 simeprevir, the first macrocyclic PI was approved for the
6,7
treatment of G1 and G4 patients. Currently several linear and
macrocyclic PIs, as faldaprevir, asunaprevir, vaniprevir and
8–10
others, are in phase II and III trials.
In addition to viral
protease inhibitors other drugs are available as first-line
treatments for Hepatitis C such as sofosbuvir (Solvadi®) and
ledipasvir-sofosbuvir (Harvoni®).
The previous standard therapy for the six viral genotypes was
based on pegylated interferon alpha and the nucleoside analog
ribavirin. However, it resulted in only 40-80% of sustained viral
response (SVR) of patients depending on the genotypes and other
factors. 2
Despite the scientific community's efforts, there is no yet an
entirely effective therapy for hepatitis C showing the need for
investigating new antivirals.
The HCV NS3/4A serine protease is a target enzyme in the
viral replication, and the protease inhibitors (PI) were the first
directly acting antiviral introduced in the therapy. In 2011,
boceprevir and telaprevir, two linear PI were approved for use in
Our group has studied peptidomimetic compounds as
inhibitors of serine protease presenting a fused bicyclic structure
11–15
from isomannide.
In previous work we synthesized series of
HCV genotype 1 infection and used in combination with
HCV protease inhibitors by introducing structural diversity at the
3,4
11,16
pegylated interferon alpha and ribavirin.
ketoamide moiety that covalently and reversibly binds the
They present an -
C-6 position of isomannide (Figure 1).
In this work we
designed two novel series of compounds derived from isosorbide
———
 Corresponding author. Tel.: +0-55-21-26299588; fax: +0-55-21-26299578; e-mail: estelamuri@yahoo.com.br

to investigate the influence of different stereochemistry patterns
on the biological activity. The first set 1a-j presenting the side
chain from oxazolone opening differs from the lead series by
changing C-3 or C-6 stereochemistry. The second series 2a-g
The final products 2a-g were obtained from the coupling
reactions of amine 6 with different N-protected amino acids using
the standard protocol DCC/DMAP for peptide bond formation
(Table 2). 16
derived from the amino acids coupling represents
a
stereochemistry change at C-3 endo to exo (Figure 1).
Table 1. Structures and yields of peptidomimetics 1a-j.
Cpd. amine
R1
X
Y
Yield
(%)
1a
1b
1c
1d
6
6
6
6
-H
-H
50
50
79
54
-H
-H
-H
-H
-H
-H
Figure 1. The design of peptidemimetics 1a-j and 2a-g from isosorbide.
Readily available isosorbide has been used as starting material
for the preparation of two amine intermediates showing distinct
configurations (6: C-3/C-6 exo; 10: C-3/C-6 endo) exploring the
different reactivities of the hydroxyl groups present at isosorbide.
The amine 6 was synthesized in a four steps sequence already
described following a tosylation and benzylation reactions of the
start material, obtaining the C-6 O-benzyl-exo/C-3 O-tosyl-endo
17–19
compound 4.
The next steps consisted in a nucleophilic
1e
1f
1g
1h
1i
6
-H
-H
-Cl
-H
-H
-H
-H
80
78
65
65
60
65
19,20
substitution followed by hydrogenation of the azido function.
For the synthesis of the unpublished amine 10 better yields were
obtained with a benzylation reaction of the C-3 endo hydroxyl
21,22
group before tosylation (Scheme 1).
Interesting our catalytic
6
-H
hydrogenation conditions to reduce the azides 5 and 9 were not
able to remove the benzyl protecting in any cases. 22,23
6
-H
6
-OCH3
-H
10
10
1j
-H
Scheme 1. Py, TsCl, 0ºC, 40h, r.t., 40%. ii: 50% KOH, TBAB, CH2Cl2,
BnCl, 3d, r.t., 95%. iii: [Bmim]+[BF4]-, NaN3, 20h, 120ºC, 68%. iv: H2, 10%
Pd/C, EtOH, 2.75 bar, 4h, 98%. v: BnCl, LiH, LiCl, DMF, 18h, 90ºC, 55%.
vi: Et3N, TsCl, 24h, r.t., 70%. vii: NaN3, DMF, 24h, 125ºC, 70%. viii: H2,
10% Pd/C, EtOH, 2.75 bar, 5h, 98%.
Initially, it was carried out tests of solubility with all
synthesized compounds where the compounds 1h, 1i, 2a, 2b, 2c,
and 2g were insoluble in the aqueous buffer used in the
enzymatic assays. The inhibitory profile of the compounds which
were soluble in the test conditions was examined concerning the
residual activity of the enzyme HCV NS3/4Apro using 100 µM
of inhibitor concentration. These initial tests showed only the
compounds 1d, 1e and 1i significantly inhibited the protease
The final products 1a-j were obtained by the ring opening of
the oxazolones previously synthesized by Erlenmeyer conditions
using the amines 6 and 10 (Table 1). 11,24,25

activity (Figure 2) with the percentage of inhibition of 30.3%,
81.8%, and 45%, respectively. Among these three compounds,
1d and 1i have not shown dose-response (data not shown), which
was observed for the compound 1e, that presented an IC50 = 36 ±
3 µM (Figure 3).
Table 2. Structures and yields of peptidomimetics 2a-g.
Cpd.
R2
Yield (%)
70
Figure 3. The representative graphic of Inhibitory potency (IC50) for 1e
against wild-type NS3/4Apro. Increasing concentrations of the compound 1e
(from 12.5 to 200 µM) were used to analyze the inhibition of the protease
activity of NS3/4A. Closed circles represent the mean of the residual protease
activity obtained in three independent experiments and bars indicate the
standard error.
2a
2b
2c
2d
50
50
60
Thus, 1e was considered the most promising compound and
was tested at 100 µM concentration against the D168A and
V170A NS3/4Apro mutants. These mutants were described as
resistant variants of the HCV NS3/4Apro to a broad spectrum of
HCV inhibitors both in vitro and in HCV patients. 15,26,27
According to figure 4, we observed that compound 1e is less
efficient against D168A in comparison with the WT (36.7% and
18.2% residual activity at 100 µM, respectively), whereas it has a
stronger effect against V170A at the same conditions (6.7%
residual activity). This result indicates that 1e is a promising
inhibitor of the HCV NS3/4A protease activity, mainly to V170A
strain.
2e
2f
65
64
74
2g
Figure 4. Inhibitory profile of 1e against the wild type (WT) HCV
NS3/4A protease and the mutants D168A and V170A at 100 µM.
To understand the activity of 1e and to identify its probable
bioactive conformation, we had performed a molecular modeling
study. Firstly, it was applied the molecular docking, from the
autodock 4.2 program, to obtain the initial structure for molecular
dynamics. From the three-dimensional structure complexed with
telaprevir (PDB: 3SV6, resolution 1.4 Å) 28, we identified the
significant subsites for the inhibition of NS3/4A and performed
the validation of the molecular docking protocol through
Figure 2. Inhibitory profile of the compounds against the HCV NS3/4A
protease at 100 µM. The relative protease activity was obtained using the
positive controls as references (reactions without inhibitor - NI). Error bars
represent the standard error obtained from three independent experiments.

molecular redocking, obtaining a pose structure with RMSD
below to 2 Å (Figure 5).
The H-bonding interactions of 1e and V170A occurs with
Arg123, Arg155, and Ala157 (S4, S2, and S3 subsites,
respectively) during the 130 ns of DM simulation. Comparing
with WT, the interactions with S2 and S4 subsites were possible
due to the appearance of the hydrophobic cavity in the S4 subsite
(Figure 6B and SD5).
Two mutations (D168A and V170A) in the pose obtained
from docking protocol were made separately followed by three
independent molecular dynamic simulations. In relation to WT
NS3/4A, it was observed a significant variation in the first 80 ns
of simulation, decreasing mobility at the binding site, with an
initial pose variation of approximately 2.5 Å (Supplementary
Data - SD1).
Figure 6. The predicted binding mode and H-bonding interactions (dash
line) of 1e in the active site of (A) WT and (B) V170A. The subsites S1’
(Yellow), S1 (Green), S2 (Blue), S3 (Pink), S4 (Orange) and S5 (Red) and
the localization of hydrophobic cavity in the S4 subsite are illustrated.
Regarding the binding free energy (ΔG binding), we have
evaluated the interaction of 1e against wild-type and V170A
strain using the MM/GBSA method for the last 10 ns of MD
simulation (Table 3).
We have observed that ΔG binding values follow the same
trend described by residual activity, where 1e is more active in
the V170A (-28.53 ± 1.94 Kcal/mol), followed by the WT (-
20.30 ± 1.98 Kcal/mol).
Figure 5. (A) 3D structural representation of NS3/4A complexed with
telaprevir. (B) Binding site divided at S1’ (Yellow; Gln41, Thr42, Phe43 and
Gly137), S1 (Green; Leu135, Lys136, Ser139 and Phe154), S2 (Blue; Hys57,
Arg155, Ala156 and Asp168), S3 (Pink; Ile132 and Ala157), S4 (Orange;
Arg123 and Val158) and S5 (Red; Ser159) subsites. (C) Superposing at
telaprevir structure extracted from 3SV6 (carbon = pink) and the redocking
results (carbon = green).
Overall, the nonpolar interactions (ΔEvdw + ΔESASA)
determine the affinity of the ligand with the WT and V170A
favoring the binding of 1e with the binding site of WT. In the
case of V170A, the increase of nonpolar interactions could be
associated with the occurrence of a hydrophobic cavity in the S4
subsite.
For the D168A, it was observed that 1e gradually exits the
binding site during the 100 ns of simulation, whereas to the
V170A, in the first nanosecond of MD simulation, the ligand
moves about 3 Å within the binding site remaining stable during
the 130 ns (SD1). Regarding the NS3 portion to WT, D168A, and
V170A, it was noted stability in the mobility with RMSD values
below 2 Å to carbon-alpha all over the MD simulation (SD1).
Table 3. Binding free energy (ΔG binding) between 1e and
wild-type (WT) and V170A enzymes.
Energy
NS3 WT
NS3 V170A
(kcal/mol)
ΔEvdw
-32.55±1.24
-5.72±1.58
26.11±1.54
-3.46±0.08
-20.30±1.98
-42.39±0.97
15.83±1.36
12.77±0.80
-4.09±0.06
-28.53±1.94
In order to understand the influence of D168A and V170A on
the affinity of 1e, the H-bonding interaction between Asp123-
Asp/Ala168 and Arg155-Asp/Ala168 were monitored (SD2).
ΔEelect
ΔEsolv
ΔESASA
ΔGbinding
The main change caused by the D168A mutation consisted of
the loss of H-bonding interaction of Asp168 with Arg123 and
Arg155 27,28, resulting in the increase the flexibility between S2
and S4 subsites (SD2B). In the case of V170A, an improvement
to Asp168 and Arg155 interactions was observed, as compared to
the wild-type enzyme (SD2A and SD2C). Interestingly, this
behavior opens a hydrophobic cavity at S4 subsite, exhibiting the
Ala166 and Val167 residues (SD2C).
We reported
a new class of small isosorbide based
peptidomimetic compounds that inhibited the HCV NS3/4A
protease. The most active compound 1e tested against the wild-
type enzyme was also evaluated in two mutant strains showing a
good inhibitory activity in the V170A assay. This is a promising
result since this NS3/4Apro mutant is resistant to several HCV
inhibitors.
The modification at binding site changes the H-bonding
interactions between 1e and WT, D168A, and V170A enzymes.
To WT NS3/4A, it was observed that the initial interactions
occur with Lys136 and Ala157, in the S1 and S3 subsites, mainly
in the last 50 ns of MD simulation (Figure 6A and SD3). The H-
bonding interaction of 1e and D168A occurs with residues
Gly137 and Ala157, in the S1’ and S3 subsites, respectively, in
the first 40 ns of simulation. After that, the interactions changed
to Ser159 (S5 subsite) and Arg161, that stayed outside of the
binding site. As these news H-bonding interactions are not strong
enough, 1e left out the binding site (SD4).
Docking and molecular dynamics studies allowed us to
identify the significant interactions between 1e and wild-type,
D168A and V170A strains. To the wild-type NS3/4A, the major
interactions occur with S1 and S3 subsites. However, it was
observed in D168A strain that the increased flexibility between
the S2 and S4 subsites contributed to the loss of inhibitory
activity. As for V170A strain, the appearance of the hydrophobic
cavity in S4 subsite favored the interactions of 1e with S2, S3,

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Acknowledgments
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18.
We gratefully acknowledge financial support from
Coordination for the Improvement of Higher Education
Personnel (Coordenação de Aperfeiçoamento de Pessoal de Nível
Superior/CAPES), National Council for Scientific and
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