Structure-Based Discovery of Nonpeptide Allatostatin Analogues for

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Agricultural and Environmental Chemistry

Structure-based Discovery of Non-peptide Allatostatin Analogs for Pest Control Shan-shan Huang, Shan-shan Chen, Hong-ling Zhang, Han Yang, Hui-juan Yang, Yujie Ren, and Zhen-peng Kai J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.8b00197 • Publication Date (Web): 23 Mar 2018 Downloaded from http://pubs.acs.org on March 23, 2018

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Journal of Agricultural and Food Chemistry 1

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Structure-based Discovery of Non-peptide Allatostatin

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Analogs for Pest Control

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Shan-shan Huang †, Shan-shan Chen ‡, Hong-ling Zhang †, Han Yang †, Hui-juan Yang , Yu-jie Ren *,†, and Zhen-peng Kai *,†

†

5 6 7

†

8

Technology, Shanghai, 201418, P.R. China

9

‡

10

School of Chemical and Environmental Engineering, Shanghai Institute of

Institute of Agro-food Standards and Testing Technologies, Shanghai Academy of agr

icultural Science, Shanghai, 201403, P.R. China

11 12 13 14

* Corresponding author

15

Email: [email protected] and [email protected]

16

ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry

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ABSTRACT：：FGLamide allatostatins (ASTs) are regarded as possible insecticide

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candidates although the absence of in vivo effects, rapid degradation, poor water

19

solubility, and high production costs, preclude their practical use in pest control. In

20

contrast to previous research, the C-terminal tripeptide (FGLa) was selected as the

21

lead

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(2-amino-1-[3-oxo-3-(substituted-anilino)propyl]pyridinium nitrate derivatives) were

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designed based on the structure-activity relationship and docking results of FGLa. All

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the non-peptide analogs (S1-5) were more potent on juvenile hormone (JH)

25

biosynthesis than the lead compound. They significantly inhibit the biosynthesis of JH

26

in vivo following injection. The pest control application demonstrated that S1 and S3

27

have larvicidal effects following oral administration (the IC50 values were 0.020 mg/g

28

and 0.0016 mg/g, respectively). Good oral toxicities and excellent water solubility of

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S1 and S3 suggest that they have considerable potential as insecticides for pest

30

management.

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KEYWORDS: Allatostatin; juvenile hormone; non-peptide analogs; oral toxicity;

32

cockroach

compound

in

this

study.

Five

non-peptide

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AST

analogs

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■ INTRODUCTION

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Insect neuropeptides have been recognized as the safe insecticide candidates

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because they play a central role in insect metabolism, homeostasis, development,

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metamorphosis, reproduction and behaviour. However, the intrinsic properties of

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insect neuropeptides, such as poor absorption, transport and bioavailability, short

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biological half-lives, lack of effect in vivo and high production costs have limited their

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application in pest control.1 The rational design of neuropeptide analogs that can

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block degradation, improve the absorption through pest cuticle and the transport in

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hemolymph was indicated as a general strategy of insect neuropeptides for control of

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pests.1

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Allatostatins (ASTs) comprise a family of insect neuropeptides originally

45

isolated from of the cockroach Diploptera punctata that inhibit the production of

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juvenile hormone (JH).2 More than 230 ASTs have been predicted from cDNA

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sequences in insects and they can be classified into three different peptide families:

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FGLamide ASTs, W(X)6Wamide ASTs

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appeared candidates on the development of pest control agents. Following the

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sequencing of FGLamide ASTs, the development of analogs quickly ensued. Previous

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structure-activity studies demonstrated that the C-terminal Y/FXFGL-NH2 is the

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‘active core’ region of the FGLamide ASTs.4 Leu8, Phe6 and Tyr4 in Dippu-AST 5

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were the crucial amino acid residues for JH biosynthesis inhibition with the Alanine

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scanning technique.5 The first, third or fifth residues of the C-terminal pentapeptide

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were substituted by sterically hindered amino acids (Aic, Cpa and Bzd) or

and PISCF ASTs.3 The FGLamide ASTs



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hydrocinnamic acid in several AST analogs. Their bioactivities showed that those

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analogs retained biological activity.6-8 Piulachs et al. synthesized ketomethylene and

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methyleneamino pseudopeptide analogs of ASTs, thereby reducing the susceptibility

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of the bond to hydrolysis.9 Garside et al. found several FGLamide AST

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peptidomimetics inhibited JH biosynthesis and oocyte growth significantly in vivo

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although the effects of injection were monitored only at one specific age.10

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In the previous studies, approximate 200 FGLamide AST analogs were

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synthesized with the C-terminal pentapeptide as the lead compound by Yang’s

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group.11-18 Their results suggested that an aromatic group, an appropriate length of

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linker, and a FGLa moiety should appear in the bioactive AST analogs. The

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subsequent study showed an alteration of the peptide backbone. This approach

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involved a replacement of the C-terminal GL region with succinic acid and

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conservation of the benzene ring.14 The highly substituted analogs show similar

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bioactivity to the lead compound.

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In contrast to previous research, the C-terminal tripeptide (FGLa) was selected as

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the lead compound in the present study. We first quantitated the biological activities

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of a series of alanine-replacement FGLa analogs to determine the residues most

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critical for the inhibition of JH biosynthesis. Based on the structure-activity

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relationship (SAR) study with alanine scanning, nine analogs that mimicked amino

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acids of the tripeptide were designed with the peptidomimetic approach by replacing

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portions of the peptides with unnatural structures. Finally, non-peptide AST analogs

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synthesized on the basis of the peptidomimetic approach. Figure 1 shows the design

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strategy. The possible applicability of these non-peptide compounds for pest control

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was demonstrated in this paper.

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■ MATERIALS AND METHODS

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Chemicals and Instruments. All the chemicals and reagents were commercially

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available. Rink Amide-AM resin (0.53 mmol/g substitution), Wang resin (1.5 mmol/g

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substitution), Fmoc-protected amino acids, Benzyloxycarbonylglycine (Z-Gly-OH),

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1-hydroxybenzotriazole anhydrate (HBTU),

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O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HOBt),

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trifluoroacetic acid (TFA), 4-dimethylaminopyridine (DMAP) and

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N,N'-diisopropylethylamine (DIEA) were purchased from GL Biochem, Ltd.

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(Shanghai, China). Thioanisole, benzaldehyde, dithioglycol, phenol,

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phenylmethanamine, (E)-cinnamic acid, hydrocinnamic acid, butanedioic anhydride,

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furan-2,5-dione, fumaric acid, butyraldehyde, 3-methylbutanal, NaBH4,

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2-aminopyridine, 2-amino-3-methylpyridine, ethyl acrylate, aniline, 2-methylaniline,

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citronellol, HPLC grade n-hexane, N,N-dimethyl-formamide (DMF), dichloromethane

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(CH2Cl2) and acetonitrile were purchased from Sigma-Aldrich (St. Louis, MO).

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Juvenile hormone III was purchased from Toronto Research Chemicals (Toronto, ON,

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Canada). Melting points were determined using a WRS-2A melting point apparatus

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(Shanghai ShenGuang Instrument Co., Ltd., Shanghai, China). Chromatographic

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separations were performed on silica gel flash columns. 1H NMR and 13C NMR



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spectra were recorded on an AVANCE III or on an Avance DMX500 spectrometer

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(Bruker, Fällanden, Switzerland) in DMSO-d using TMS as an internal standard.

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HRMS were recorded on a solariX 70 FT-MS spectrometer (Bruker) using

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methanol/water (1:1, v/v) as solvent. LC-mass spectra were recorded on a

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LCMS-2020 spectrometer from Shimadzu Corporation (Kyoto, Japan). The structures,

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purity, and MS data of all target compounds are shown in Figure 1, Table 1 and 2.

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Synthesis of peptides and peptidomimetics. Five tripeptides (FGLa, AGLa,

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FALa, FGAa and FGL) were synthesized from Rink Amide-AM resin (189 mg, 0.1

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mmol) or Wang resin (67 mg, 0.1 mmol) using the standard Fmoc/tBu chemistry and

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HBTU/HOBt protocol.12 Compounds of series A, B and C were syntheiszed with the

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methods previously reported.13,14 The structures of peptides were confirmed by the

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molecular ions (Table 2). All of the crude peptides and peptidomimetics were purified

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on a C18 column with a flow rate of 10 mL/min using acetonitrile/water (50:50)

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containing 0.06% TFA as an ion-pairing reagent.

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Synthesis of 2-amino-1-[3-oxo-3-(substituted-anilino)propyl]pyridinium

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nitrate derivatives (General Procedure for designed compounds ).

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2-Aminopyridine or 2-amino-3-methylpyridine 1 (10 mmol) and ethyl acrylate 2 (15

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mmol) were mixed in a dry round-bottom flask and five drops nitric acid was added.

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The mixture was heated to 100 oC and stirred for 2 h under a nitrogen atmosphere.

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After reaction completion, ethyl acetate/petroleum ether (2:3, v/v) was added. The

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unreacted ethyl acrylate and solvent were removed under vacuum, and a light yellow

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solid was obtained. Substituted anilines 4 (10 mmol) and ethanol were then added to


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the round-bottom flask. The mixture was heated to 95 oC and stirred for 24 h under a

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nitrogen atmosphere. After reaction completion, the mixture was adjusted to pH 7.0

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with NaOH solution. The solvent was removed under vacuum. The products were

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purified by column chromatography using a mixture of CH2Cl2/MeOH (20:1).19All

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the structure elucidation data are presented in Table 1 and 2.

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Insect. Animals fed Lab Chow and water ad libitum were kept at 27±0.5 °C,

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50±5% RH. Newly emerged (Day 0) mated female D. punctata were isolated, placed

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in containers and provided with food and water.

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Bioassays for JH III in vitro. A pair of corpora allata from day 7 mated

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D. punctata were incubated for 3 h at 30 °C in medium 199 (GIBCO, 100 µL) with

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Hanks’ salts, L-glutamine, 25 mM HEPES buffer (pH 7.2) and 2% Ficoll in the dark

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with gentle shaking. After incubation, 20 ng of citronellol was added to the medium as

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an internal standard. 200 µL n-hexane was mixed with the incubation medium and the

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mixture was centrifuged for 5 min, then the n-hexane phases were transferred to new

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analytical vials. The measurement of JH III was determined using gas

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chromatography tandem mass spectrometry as described previously.20 The retention

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time of JH III was 10.36 min. The quantification transition for JH II was 85.1→59.1

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(collsion energy: 10 eV). The confirmation transitions were 81→79.1 (collsion energy:

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5 eV), 94.9→67.1 (collsion energy: 10 eV), 120.9→93 (collsion energy: 10 eV) and

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120.9→105.1 (collsion energy: 15 eV), respectively.

141 142

Bioassays for JH III in vivo. Females were injected with 5 µL of FGLa, designed analogs (1 µM) using a 10 µL syringe on day 1, and the hemolymph JH III



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concentration determined on day 3. Control insects were similarly injected, but with 5

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µL of double distilled water. For the hemolymph collection, a volume of 50 µL

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hemolymph was immediately transferred to a glass centrifuge tube containing 50 µL

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acetonitrile, 50 µL 0.9% sodium chloride solution and 20 ng of citronellol. The

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sample was extracted twice with 100 µL hexane. The organic phase was transferred to

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a new glass vial. The quantity of JH III was determined as above.

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Assays for impact of feeding on D. punctata mortality. Three groups of D.

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punctata were used for feeding assays. The initial populations of each group were

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made up of 100 newly hatched larvae. These larvae were fed with standard laboratory

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cockroach food that had been treated with designed compounds (S1-5) (> 95% pure,

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the concentration was 0.1 mg/g, 0.01 mg/g, 0.001 mg/g and 0.0001 mg/g,

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respectively). Treated food was made by adding 1 mL of a stock solution containing

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designed compounds dissolved in water, to 1 g of food. The excess solvent was

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evaporated while the food was continuously stirred to ensure the even distribution of

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AI in the bait.21 The experimental units were maintained in a room at 27±0.5 °C, 50±5%

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RH and 12/12 h light/dark photoperiod. Larval mortality were recorded every day

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after treatment.

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■ RESULTS AND DISCUSSION

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Design and bioactivities of analogs in vitro. In this study, a tripeptide, FGLa,

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was synthesized as the lead compound. Treatment with FGLa showed a significant

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effect on JH biosynthesis in vitro (the IC50 value was 2.06 µM). It demonstrates that


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the C-terminal tripeptide could be the lead. The alanine scan is a common method to

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define the crucial residues and has proven useful in characterizing the SARs of several

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insect neuropeptide including allatostatin.5,22 We determined the amino acids of the

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lead compound FGLa that are most critical for bioactivity by replacing alanine for

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each residue. Their potencies in the in vitro assay are shown in Table2. AGLa ([Ala1]-

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FGLa) and FGAa ([Ala3]-FGLa) were completely inactive, even at a concentration of

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10 µM. Assay of FALa ([Ala2]-FGLa) showed that this analog had an effect on JH

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biosynthesis (IC50: 37.58 µM), but was 18-fold less potent compared with FGLa. We

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also synthesized FGL, which shares the same sequence with FGLa but without the

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C-terminal amide to validate the function of the C-terminal amide. Analog FGL did

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not show any bioactivity on JH biosynthesis. It suggested that the side chain of Phe1,

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Leu3 and the C-terminal amide of lead compound are crucial for JH biosynthesis.

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We built the three-dimensional structure of AST receptor23 of D. punctata by

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homology modeling using the crystal structure of the nociceptin/orphanin FQ receptor

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as the template and identified the ligand-binding pocket using blind docking

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calculations. Figure 2A shows the C-terminal amide of FGLa forms hydrogen bond

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with His336 of receptor. The benzene ring of the residue Phe of FGLa has a π-π

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interaction with the benzene ring of Tyr253 (Figure 2A). The hydrophobicity of the

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binding pocket was shown in Figure 2B. It indicated the Phe and Leu of FGLa had

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strong hydrophobic interactions with the receptor. The docking result was consistent

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with the results of our biological assays. It also can explain why the biological activity

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is lost during the replacement.



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Based on the Ala-replacement and docking results, analogs of series A, B and C

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that mimicked residues of the lead compound were designed by replacing portions of

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the peptides with unnatural amino acids.

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In series A, aromatic acids were used as mimics of the residue Phe. In

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comparison to the lead, these analogs showed similar inhibition of JH biosynthesis

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(Table 2). In the structures of B1, 3-(benzylcarbamoyl)propanoic acid was used to

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mimic the FG sequence. Compared with the lead compound tripeptide, B1 improved

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the effect on JH inhibition (IC50 value: 0.48 µM). Structural studies on ASTs showed

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flexible conformations in aqueous solution.24,25 There is considerable debate on the

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actual active conformation: turn or linear. Two trans-cis isomers (a

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restricted-linear-conformation mimic B2 and a restricted-turn-conformation mimic B3)

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were synthesized with the purpose of probing the potential active conformations

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(Figure 1). The trans-isomer of tripeptide mimic (B2) can inhibit JH biosynthesis in

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vitro, whereas the cis-isomer one (B3) has no effect on inhibition (Table 2). The

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bioassay results of the two cis-trans isomers support the linear conformation model.

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The docking results (Figure 2) also showed that the FGLa was docked into the AST

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receptor model in the linear conformation. The effect of B2 is 9-fold less than that of

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FGLa, as the restricted plane in B2 may affect the position of the important

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pharmacophore (benzene ring and L-leucine) and debase its bioactivity. Appropriate

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conformation flexibility should be considered in the further analog design. In series C,

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substitution of Leu with benzylamine, n-butylamine and isopentylamine demonstrated

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little inhibition of JH biosynthesis by C1 (19-fold) relative to FGLa, and C2 and C3


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showed no effect on JH biosynthesis (Table 2). The C terminus (CONH2) was ignored

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in series C. The bioactivity of series C compounds suggesting that the hydrogen bond

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of the C terminus with the receptor is important to AST activity. Thus, in the potent

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FGLa analog, the benzene ring of Phe region should be conserved, the side chain of

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Leu region can be replaced by aromatic groups, and the C-terminal NH2 cannot

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readily be reduced.

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According to the above results, the five analogs

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designed (Figure 1). In designed compounds, the points of synthetic modification

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included (1) conservation of the benzene ring of Phe and the C-terminal amide, (2)

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replacement of Leu with pyridinium, (3) connection of all the three effective groups

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with a flexible linker propanamide segment. On the basis of the IC50 values, all the

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designed compounds are more potent than the lead compound FGLa (Table 2).

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Particularly, the compound S1 had the same IC50 value as some natural ASTs, such as

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Dippu-AST 3 and Dippu-AST 13 (IC50:0.018 µM and 0.020 µM , respectively).26

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Figure 3 shows the compound S1 has the similar interactions as FGLa with the AST

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receptor. In addition, the pyridinium ring of designed analogs , a π-π interaction with

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Trp307, which can explain the higher bioactivity of these compounds (Figure 3). The

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water solubility of these analogs is better than the lead compound FGLa (a peptide of

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3 hydrophobic amino acids), because they are the pyridinium nitrate derivatives.

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Effect of designed analogs on JH biosynthesis in vivo. Following injection of the

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designed analogs into newly emerged female D. punctata, JH biosynthesis was



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assayed after 3 d with significant inhibitory effects apparent (Figure 4), whereas the

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lead peptide FGLa was inactive in vivo. Assuming a hemolymph volume of 50 µL for

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day 1 adult female D. punctata,27 the final concentrations of the injected analog in the

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hemolymph were approximately 100 nM. The inhibition of compounds S1, S2, S3, S4

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and S5 was 81.1 ± 1.8%, 76.8 ± 4.4%, 71.0 ± 6.0%, 71.3 ± 4.1% and 43.9 ± 6.6%,

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respectively.

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Pest control application. Insect neuropeptides offer potential candidates for the

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development of novel eco-friendly insecticides. However, they have a number of

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characteristics that make them rather unsuitable for pest control, such as unstable in

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the environment, poor solubility and rapid degradation in the digestive system of

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insects. ASTs only have effects (reducing the growth of oocytes or JH in the

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haemolymph in certain cockroaches) by injection at very high and sometimes in

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repeated doses.28,29 We have synthesized an AST mimic, H17, which shows a highly

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significant inhibition of JH production in topical cuticular assays in vivo.11 There is no

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insecticidal AST mimic mainly absorbed in stomach up to now. Oral toxicity is

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crucial for the pest control application. Hence an oral toxicity test with designed

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compounds was performed in this study. The results of the experiments in which the

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larval mortality of D. punctata were exposed to designed compounds treatments are

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shown in Figure 5. S1 and S3 have significant larvicidal effects following oral

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administration with high mortality (81.0 ± 5.6% and 100%, respectively) at the

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concentration of 0.1 mg/g, whereas compounds S2, S4 and S5 are inactive in this

251

experiment. The larval mortality of JH mimic fenoxycarb and anti-JH compound


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pitavastatin30 at the same concentration were 79.3 ± 3.7% and 32.7 ± 2.0%,

253

respectively. The dead larvae appeared seven days after the treatment with molting

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disturbances. In the oral toxicity assay, the IC50 values of S1 and S3 were 0.020 mg/g

255

and 0.0016 mg/g, respectively. Structural modifications to the phenyl group indicate

256

that the electron-donating groups maintained the bioactivity. However, the

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electron-withdrawing group completely eliminated the insecticidal activity. The

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bioassay results for the compound S3 indicated that the introduction of a meta-

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electron-donating group in the phenyl group enhanced the oral toxicity against the

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cockroach.

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In

conclusion,

novel

non-peptide

AST

analogs

262


263

synthesized with the C-terminal tripeptide of the FGLamide ASTs as the lead

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compound. All the designed compounds have significant effects on JH biosynthesis

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both in vitro and in vivo. Good oral toxicities of compounds S1 and S3 suggest that

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they have considerable potential as insect growth regulators for pest control.

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Furthermore, good water solubility of these designed compounds makes them easier

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to formulate as insecticides.

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AUTHOR INFORMATION

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Corresponding Authors

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* Tel.: +86-13671951027. Fax: +86-21-60877220. E-mail: [email protected] (Z.P.K).

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* Tel.: +86-2160877231. Fax: +86-2160877231. Email: [email protected] (Y.J.R).

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Notes

275

The authors declare no competing financial interest.

276

Funding Sources

277

This work was supported by grants from the National Key Research and Development

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Plan of China (No. 2017YFD0200504) and Shanghai Municipal Science and

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Technology Commission (17142201300).

280

Supporting Information

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Synthesis of peptides, series A, B and C peptidomimetics. Homology modeling of

282

Dippu-AstR, docking calculations and molecular dynamics simulations of FGLa and

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analogs.

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Figure 1. Design of FGLa analogs.

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Figure 2. Binding sites of FGLa in D. punctata AST receptor. (A) The hydrogen bond

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and π-π interactions of FGLa with receptor. (B) The hydrophobicity of the binding

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pocket. Hydrogen bond is shown with dotted yellow line.

391 392

Figure 3. The same hydrogen bond and π-π interactions of FGLa and the compound

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S1 with AST receptor. FGLa is shown with purple stick and the compound S1 with

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orange stick. Hydrogen bond is shown with dotted yellow line.

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Figure 4. JH biosynthesis following injection of FGLa and compounds S1-5. Females

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were injected with 5 µL of compound (1 µM) using a 10 µL syringe on day 1, and

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hemolymph JH III titer determined on day 3. Values represent mean ± s.e.m., ****p

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