Sulfono-γ-AA modified peptides that inhibit HIV-1 fusion

Article abstract of DOI:10.1039/c8ob02159g

The utilization of bioactive peptides in the development of highly selective and potent pharmacological agents for the disruption of protein-protein interactions is appealing for drug discovery. It is known that HIV-1 entry into a host cell is through a f

Full text of DOI:10.1039/c8ob02159g

Organic &
Biomolecular Chemistry
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Sulfono-γ-AA modified peptides that inhibit HIV-1
fusion†
Cite this: Org. Biomol. Chem., 2018,
16, 7878
a
Olapeju Bolarinwa, a Meng Zhang,b Erin Mulry,a Min Lu*b and Jianfeng Cai
*
The utilization of bioactive peptides in the development of highly selective and potent pharmacological
agents for the disruption of protein–protein interactions is appealing for drug discovery. It is known that
HIV-1 entry into a host cell is through a fusion process that is mediated by the trimeric viral glycoprotein
gp120/41, which is derived from gp160 through proteolytic processing. Peptides derived from the HIV
gp41 C-terminus have proven to be potent in inhibiting the fusion process. These peptides bind tightly to
the hydrophobic pocket on the gp-41 N-terminus, which was previously identified as a potential inhibitor
binding site. In this study, we introduce modified 23-residue C-peptides, 3 and 4, bearing a sulfono-γ-AA
residue substitution and hydrocarbon stapling, respectively, which were developed for HIV-1 gp-41
N-terminus binding. Intriguingly, both 3 and 4 were capable of inhibiting envelope-mediated membrane
fusion in cell–cell fusion assays at nanomolar potency. Our study reveals that sulfono-γ-AA modified pep-
tides could be used for the development of more potent anti-HIV agents.
Received 1st September 2018,
Accepted 1st October 2018
DOI: 10.1039/c8ob02159g
rsc.li/obc
mimetics8 have been developed for the inhibition of viral entry
and fusion. However, peptides derived from N-HR mostly show
Introduction
The global HIV statistics of 2015 revealed that approximately weak inhibitory activities if the design does not promote tri-
36.7 million people worldwide are living with the human merization of N-HR peptides.4,9 Only typical N-HR constructs
immunodeficiency virus (HIV) and over 2.1 million new cases
of HIV infection were recorded annually.1,2 During the mem-
brane fusion process, gp41 of HIV forms a fusion-active six-
helix bundle (6-HB) with a hydrophobic pocket.3 In this six-
helix bundle, the amino-terminal heptad repeat (N-HR) forms
a central trimeric coiled-coil core, whereas the trimeric helical
carboxy-terminal heptad repeat (C-HR) wraps around and
interacts with it in an antiparallel mode.4 This six-helix bundle
brings the viral and host cell membranes into close proximity
and facilitates their fusion.5 The mutual dependence of N-HR
and C-HR on each other in the 6-HB formation during viral
entry makes them very important targets for fusion inhibitor
design (Fig. 1A). Indeed, targeting the viral entry and fusion
process of an enveloped virus remains a very appealing thera-
peutic strategy due to its relative accessibility. Potent inhibitors
which block these specific interactions that are mandatory for
HIV-1 viral entry have been reported. For instance, small mole-
cules,6 engineered peptides7 and artificially designed peptido-
aDepartment of Chemistry, University of South Florida, 4202 East Fowler Avenue,
Tampa, Florida 33620, USA. E-mail: jianfengcai@usf.edu
bPublic Health Research Institute, Department of Microbiology, Biochemistry and
Molecular Genetics, Rutgers Biomedical and Health Sciences, Newark, New Jersey
07103, USA. E-mail: lum1@njms.rutgers.edu
Fig. 1 (A) Schematic illustration of the different regions of HIV-1 gp41.
FP: fusion peptide, N-HR: N heptad repeat, C-HR: C heptad repeat,
MPER: membrane proximal ectodomain region, TM: transmembrane
region, and CP: cytoplasmic domain and (B) C-HR derived peptides. “X”
shows the position of the hydrocarbon staple; “γK” is sulfono-γ-AA1.
Peptide 1 is MT-SC22EK and was first reported in ref. 16b.
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8ob02159g
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forming stable trimers can efficiently target HIV-1 fusion.10 As
a result, C-HR derived peptides have been studied extensively
in the therapeutic search for potential fusion inhibitors.
Examples include α-helical peptides such as enfuvirtide
(T20)11 and C34 (Fig. 1B).12
Enfuvirtide obtained market approval as the only HIV-1
fusion inhibitor for clinical use and it works by competitively
binding the N-HR, thereby blocking the formation of the
six-helix bundle required for fusion. It is very active against
various HIV-1 strains including those resistant to reverse tran-
scriptase and protease inhibitors.11b,13 It is similar in design
to a segment of C-HR comprising amino acids 127 to 162 of
the C-terminal end (Fig. 1B).14 Although T20 has great anti-
HIV activity, it is prone to induce drug resistance through
mutations within the N-HR sites. Additionally, its poor bio-
availability and large dose requirements complicate its thera-
peutic use.15 Similar to T20, C34 also has sequence homology
with C-HR. Due to a 22-amino acid overlap between T-20 and
C34 peptides, HIV-1 has also developed major mutations for
C34 resistance in vitro.15b
To overcome the problems posed by T20 and other similar
HIV fusion inhibitors, great efforts have been made to opti-
mize the fusion inhibitors derived from the C-HR helical
region of gp41 in order to suppress the emergence of resistant
strains and increase the in vivo stability and N-HR binding
affinity.16 One approach is to introduce electrostatic con-
straints into peptides to improve the helicity and antiviral
activity profile. This entails the substitution of charged and
hydrophilic amino acids such as glutamic acid (E) and lysine
(K) at i and i + 4 positions in the solvent-accessible site of C34
and its short variants.3b,17 In a six helix bundle, C-HR interacts
with N-HR at the amino acid residues at the a and d positions
of the heptad repeat (Fig. 2A & C). These residues are known to
be critical for molecular recognition between both heptad
repeats, while residues at positions b, c, f and g are exposed to
the solution and are almost non-crucial for gp41 C-HR and
N-HR interactions (Fig. 2A).5a However, the residues at these
positions are very critical for solubility and stability and they
Fig. 2 A. Schematic illustration of the helical wheel of the C-terminal
heptad repeat of gp-41. B. General structures of α-peptides,
γ-AApeptides and sulfono-γ-AApeptides. C. Schematic illustration of the
positioning of the hydrocarbon staple and sulfono-γ-AA1.
have great effects on the in vivo activity and druggability of D-peptides,8d,10a unnatural foldamers,20 and covalently
the peptide fusion inhibitors. These engineered electrostatic restrained α-helices.8b,c,21 These peptide mimics have gener-
interactions are helix enhancers and have significantly ated highly potent fusion inhibitors with outstanding in vivo
improved the solubility, helicity and potency of such derived stabilities.
peptides.3b,17a,b,18 Effects on the antiviral activity of the
Sulfono-γ-AApeptides are a sub-class of γ-AApeptides that
improved helicity of C-peptide variants have been well docu- are oligomers of N-acylated-N-aminoethyl amino acids.22 The
mented.17a–c It is believed that the ability of the derived C-HR replacement of carboxylic acids with sulfonyl chlorides in
peptides to adopt stable helical conformation upon interaction γ-AApeptides produces sulfono-γ-AApeptides (Fig. 2B). They
with the N-HR fosters the formation of the six helix bundle have enormous potential in functional group diversity. Like
(6-HB) by increasing the binding affinity and in vivo stability. γ-AApeptides, sulfono-γ-AApeptides are able to display the
This in turn increases the anti-HIV activity.17c
same number of side chains as conventional peptides of equal
An additional approach is to introduce conformational length, endowing them with the ability to mimic bioactive pep-
restraints by substitution with non-proteinogenic amino acids tides. As evidenced by their crystal structures, sulfono-
at the solvent-exposed site of C-HR derived peptide mimics. γ-AApeptides possess an intrinsic folding propensity which is
For instance, peptidomimetics with unnatural amino acids most likely a result of the bulkiness of the tertiary sulfonamide
and building blocks have been reported to successfully mimic group and intramolecular hydrogen bonding.23 Their optical
the molecular interaction between gp41 C-HR and analysis by circular dichroism and 2D-NMR also supports their
N-HR.8,14b,16b,c,19 Peptide mimics that target gp41 N-HR include well-crafted helical conformation.23 To explore the potential of
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sulfono-γ-AApeptides for their ability to modulate HIV-1 fusion (Fig. 1B and Table 1). We further developed 2 (control) and 4. 2
at the cell entry stage, we designed two peptides (3 & 4) con- and 4 are stapled variants of 1 and 3, respectively. 3 contains a
taining sulfono-γ-AA residues. Our previous findings suggested sulfono-γ-AA1 residue (γK) at the 22nd position, while 2 and 4
that replacement of amino acid residues with sulfono-γ-AA contain hydrocarbon staples between residues X at the 4th and
residues could retain sequence helicity.24 Thus, we envisioned 8th positions (Fig. 2C and Table 1). Our decision to install the
that these sequences were still capable of mimicking gp41.
hydrocarbon staple at the N-terminus was inspired by a previous
report by Bird et al. They ranked the order of antiviral activities
of the hydrocarbon stapled lengthy peptides as follows: double
stapling > N-terminus single stapling > C-terminus single
stapling.21
Results and discussion
Peptide 1 is a 24-residue electrostatically constrained C-HR
derived peptide with the MT-hook structure (Table 1), which
was previously reported to be an active fusion inhibitor.16b
Thus, it was used as the template sequence for modification
(Fig. 1B).16b At first, we substituted all the “EE” and “KK”-
motifs in peptide 1 with “γE” and “γK”, respectively (Table S2
and Fig. S4†). The resulting peptide, P1, exhibited poor helicity
and antiviral activity (Table S2 and Fig. S5†). We hypothesized
that substitution of too many amino acid residues with
sulfono-γ-AA residues disrupts the secondary structure of 1.
This led us to limit our point of substitution to either the N- or
the C-terminal end, resulting in peptides P3 and P4. Similar to
P1, P3 and P4 displayed poor antiviral activities and helicities
(Table S2, Fig. S5†). We believed that inserting both “γE” and
“γK” in the same sequence could sufficiently affect the folding
propensity of 1. We then decided to study the effects of “γK”
substitution on the helicity and antiviral activity of 1. We
designed peptides 3 (Fig. 1B) and P2 (Table S2†) with “γK” sub-
stitution at various points on the C-terminal end. To our sur-
prise, 3 showed similar antiviral activity to 1 (Table 2).
However, P2 displayed poor antiviral activity and poor helical
propensity (Table S2, Fig. S5†). As such, our attention was paid
to the development of 3.
We next first conducted CD studies to assess the helical pro-
pensities of the sequences. As shown in Fig. 3A, both 1 and 3
exhibited comparable helical folding propensities with charac-
teristic minima at both 207 and 222 nm suggesting the exist-
ence of probable α-helical conformation. This suggests that
incorporation of sulfono-γ-AA residue did not alter helicity sig-
nificantly. As expected, after hydrocarbon stapling, both 2 and
4 clearly showed a significant increase in helicity compared to
their unstapled counterparts, 1 and 3 (Fig. 3A). This is consist-
ent with the previous findings that i, i + 4 hydrocarbon sta-
pling enhances the α-helicity of peptides.21,25,26 These findings
are corroborated by thermal stability studies (Fig. 3B). 1 and 2
showed similar behavior at high temperature. However, 1 is
more stable than 2 at temperatures lower than 35 °C. Also, 4
demonstrated increased stability than 3. Overall, hydrocarbon
stapling improved the helicities and thermal stability profiles
of 2 and 4.
We then examined the antiviral activities of these sulfono-γ-AA
containing peptides by a HIV neutralization assay (Table 2).27
Conformationally stabilized pre-formed recombinant env
trimers derived from various subtypes of HIV-1 strains were
used in the assay.28 Both (enfuvirtide) T20 and AZT were also
tested for comparison. Interestingly, both 3 and 4 displayed
similar antiviral activities across the various strains tested.
1 and 2 also showed a similar trend in antiviral activity.
In order to optimize our design, we sought to improve the
helicity of 3 by employing a combination of sulfono-γ-AA
residue substitution (γK) and single hydrocarbon stapling
However,
3 displayed increased antiviral activity (<2-fold)
than 1. This indicates that the introduction of the peptidomi-
metic monomer, sulfono-γ-AA1, slightly improved the inter-
action of peptide 3 with the N-HR of gp41, resulting in the
inhibition of six-helix bundle formation. It is worth noting that
antiviral activity is not strictly dependent on secondary struc-
tures as evidenced by the obtained results (Table 2), as 3 and 4
exhibited comparable antiviral activities, just like 1 and 2. All
tested peptides showed comparable or greater anti-HIV activities
Table 1 List of peptides and modifications
Peptide
Sequence
Modification
1
2
3
4
MTWEEWDKKIEEYTKKIEELIKKS
MTW EWD KIEEYTKKIEELIKKS
MTWEEWDKKIEEYTKKIEELI
MTW EWD KIEEYTKKIEELI
—
Hydrocarbon stapling
Sulfono-γ-AA1 (γK)
Both
S
S
Table 2 Antiviral activity from the HIV neutralisation assay
IC50a (nM)
CZA97
6.8 1.6
7.6 1.0
4.6 0.1
6.5 0.8
941.0 328.3
184.6 26.4
B41
BG505
SF162
MN
DU422
1
2
3
4
T20
AZT
181.1 89.1
210.8 58.9
118.8 4.0
171.3 4.6
214.6 16.2
106.4 16.8
15.2 0.2
14.0 0.5
9.0 0.2
9.7 2.6
18.4 10.1
84.0 1.8
11.3 2.2
15.6 0.9
7.2 1.8
11.4 0.8
23.9 2.1
109.6 23.5
102.4 29.9
67.1 9.1
77.9 2.4
51.2 10.2
6.5 0.6
14.8 0.3
16.0 1.1
6.0 2.7
11.3 0.1
56.0 1.6
183.3 1.9
194.1 1.6
a Antiviral activity shown as the IC50 was determined by the HIV neutralization assay. Each IC50 value represents the mean SEM obtained from
at least two independent experiments.
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exhibited almost similar resistance to proteolytic degradation
as 1, indicating that the introduction of unnatural residues
could enhance the stability of the sequence.
Conclusions
To summarize, although the daunting challenges hampering
the clinical applications of enfuvirtide (T20) have limited the
repository of active peptide-fusion inhibitors, the possibility of
incorporating non-natural scaffolds may ultimately usher in a
new generation of peptide-fusion inhibitors with great thera-
peutic potential and improved protease resistance. Although
our current design did not yield peptides with enhanced stabi-
lities toward proteolysis, our study reveals that sulfono-γ-AA
modified peptides could be used for the development of more
potent anti-HIV agents. Furthermore, it is known that homo-
geneous sulfono-γ-AApeptides are completely resistant to enzy-
matic degradation and they possess remarkable helical pro-
pensities. We envision that we could use homogeneous
sulfono-γ-AApeptides to design HIV-1 gp41 mimetics in the
future. Additionally, the strategy implemented herein not only
provides ideas for future HIV-1 inhibitor design, but may also
be explored for protein–protein interaction inhibitor (PPII)
design.
Conflicts of interest
Fig. 3 (A) CD spectra of peptides 1–4. (B) Change in mean residue
There are no conflicts to declare in this work.
ellipticity [θ]222nm for peptides 1–4 as
a function of temperature
(5–70 °C). Conditions – pH 7, 25 °C, solvent – H2O.
Acknowledgements
We acknowledge the support from NIH 1R01GM112652-01A1.
than enfuvirtide (T20), a fusion inhibitor, and AZT, a reverse
transcriptase inhibitor, which are currently being used in the
clinics for the treatment of the symptomatic disease (Table 2).
Thus, 3 emerged to be the most active peptide with the best
antiviral activity across all strains tested (<2-fold increase).
To directly interrogate the effect of sulfono-γ-AA1 substi-
tution and hydrocarbon stapling on proteolytic cleavage, we
used LC/MS to identify proteolytic fragments generated by the
digestion of our peptide panels with chymotrypsin. After
10 min, 1, 2 and 4 demonstrated greater stabilities to chymo-
trypsin than 3 (Table 3 and Fig. S6†), suggesting that the
inclusion of the sulfono-γ-AA residue slightly altered the heli-
city, making it easier to be hydrolyzed. However, after back-
bone stapling, still possessing one sulfono-γ-AA residue, 4
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