Eco-Friendly Insecticide Discovery via Peptidomimetics: Design

Apr 26, 2015 - ... activity of a series of cephalomyotropic neuropeptides, the achetakinins, on isolated Malpighian tubules of the house cricket J. In...
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Eco-Friendly Insecticide Discovery via Peptidomimetics: Design, Synthesis, and Aphicidal Activity of Novel Insect Kinin Analogues Chuanliang Zhang,† Yanyan Qu,‡ Xiaoqing Wu,† Dunlun Song,‡ Yun Ling,† and Xinling Yang*,† †

Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, P. R. China Department of Entomology, College of Agronomy and Biotechnology, China Agricultural University, Beijing 100193, P. R. China

‡

ABSTRACT: Insect kinin neuropeptides are pleiotropic peptides that are involved in the regulation of hindgut contraction, diuresis, and digestive enzyme release. They share a common C-terminal pentapeptide sequence of Phe1-Xaa2-Yaa3-Trp4-Gly5NH2 (where Xaa2 = His, Asn, Phe, Ser, or Tyr; Yaa3 = Pro, Ser, or Ala). Recently, the aphicidal activity of insect kinin analogues has attracted the attention of researchers. Our previous work demonstrated that the sequence-simplified insect kinin pentapeptide analogue Phe-Phe-[Aib]-Trp-Gly-NH2 could retain good aphicidal activity and be the lead compound for the further discovery of eco-friendly insecticides which encompassed a broad array of biochemicals derived from micro-organisms and other natural sources. Using the peptidomimetics strategy, we chose Phe-Phe-[Aib]-Trp-Gly-NH2 as the lead compound, and we designed and synthesized three series, including 31 novel insect kinin analogues. The aphicidal activity of the new analogues against soybean aphid was determined. The results showed that all of the analogues exhibited aphicidal activity. Of particular interest was the analogue II-1, which exhibited improved aphicidal activity with an LC50 of 0.019 mmol/L compared with the lead compound (LC50 = 0.045 mmol/L) or the commercial insecticide pymetrozine (LC50 = 0.034 mmol/L). This suggests that the analogue II-1 could be used as a new lead for the discovery of potential eco-friendly insecticides. KEYWORDS: eco-friendly insecticide discovery, peptidomimetics, synthesis, insect kinin analogues, aphicidal activity

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required for activity and the “active core” region of insect kinins and/or their analogues. Following replacement of the Cterminal amide with a negatively charged acid moiety, the myotropic and diuretic activity in assays with cockroach tissues and bioluminescence response in CHO-K1 cells expressing kinin receptors are entirely lost.14,19−22 In addition, using the Ala scanning technique, Roberts et al.23 showed the importance of Phe1 and Trp4 side chains. Analogues in which these two positions were replaced with Ala lost activity in myotropic and diuretic assays and bioluminescence response on mosquito and tick receptor-expressing systems.19,21 Furthermore, this study demonstrated that the positions Xaa2 and Yaa3, especially Xaa2, tolerated a range of chemical characteristics, from acidic to basic residues and from hydrophilic to hydrophobic groups. Analogues with aromatic residues at this position (Xaa2) showed the highest potency in Malpighian tubule fluid secretion assays.23 The peptidomimetic approach, replacing sections of peptides with natural/unnatural structures to overcome the limitations of natural peptides while retaining biological activity, is a widely used method in the discovery of peptide-based pharmaceuticals.24−27 Likewise, developing peptidomimetic analogues of natural active peptides with potential insecticidal activity is also a feasible strategy to discover new insecticides. Nachman et al.10,19,28 incorporated sterically hindered α, α-disubstituted amino acids, α-amino-isobutyric acid (Aib), anamethyl-phenylalanine residue (α-Me Phe), and β-amino acid into natural

INTRODUCTION The first member of the insect kinin neuropeptides was isolated from the cockroach Leucophaea maderae on the basis of the myostimulatory activity on hindgut contraction. Later studies identified this family of neuropeptides in many insects.1−4 The insect kinin neuropeptides share a common conserved Cterminal pentapeptide sequence Phe1-Xaa2-Yaa3-Trp4-Gly5-NH2 (where Xaa2 = His, Asn, Phe, Ser, or Tyr; Yaa3 = Pro, Ser, or Ala).5,6 They exhibited pleiotropic functions including diuretic activity to stimulate the secretion of primary urine by Malpighian tubules, the regulation of hindgut contraction, and digestive enzyme release.4,7−11 Because of their activity in inhibiting weight gain in larvae of two serious pest insects, the tobacco budworm Heliothis virescens and the corn earworm Helicoverpa zea, the peptides have been proposed to be potentially useful in the integrated pest management (IPM) and considered as the lead for the discovery of a novel ecofriendly insecticide.10,12−15 Although kinin neuropeptides show multiple functions, they have several shortcomings as potential pesticides, mainly because of their susceptibility to both exo- and endopeptidases in hemolymph and tissues of insects. Nachman et al.10 have reported two susceptible hydrolysis sites in the core pentapeptide sequence Phe1-Tyr2-Pro3-Trp4-Gly5-NH2. The primary cleavage site is between the Pro3 and the Trp4 residue, susceptible to both angiotensin converting enzyme (ACE) from the housefly and neprilysin (NEP); the secondary site is the Nterminal to the Phe1 residue, susceptible to NEP.10,16−18 To find analogues that retain activity but overcome these limitations, studies on the primary structure−activity relationships have been carried out in recent years. The C-terminal pentapeptide is considered to be the minimum sequence © 2015 American Chemical Society

Received: Revised: Accepted: Published: 4527

March 10, 2015 April 25, 2015 April 26, 2015 April 26, 2015 DOI: 10.1021/acs.jafc.5b01225 J. Agric. Food Chem. 2015, 63, 4527−4532

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Journal of Agricultural and Food Chemistry

Figure 1. Design strategy of the insect kinin analogues using the peptidomimetic approach.

insect kinin sequence. These analogues not only maintain their activity in vitro in A. domesticus and A. aegypti Malpighian tubule fluid secretion assays and activity in vivo in M. domestica diuretic assay but also retain their resistance to hydrolysis of ACE and NEP endopeptidases. In addition, these analogues showed a response in receptor-expressing systems of tick Boophilus microplus and A. aegypti.10,18,19,28 Among these analogues, the double Aib-containing kinin analogue (K-Aib-1: Aib-Phe-PheAib-Trp-Gly-NH2) was first reported to exhibit good aphicidal activity against pea aphid Acyrthosiphon pisum.13 However, this analogue is still not suitable for use as an insecticide as a result of its longer peptide chain, higher molecular weight, and lower aphicidal activity. Further studies need to be undertaken to discover better kinin analogues with simpler structure and higher activity. In our previous work, we designed and synthesized a series of analogues using K-Aib-1 as the lead compound, modifying the N-terminal by replacing the N-terminal Aib with different substitutes or completely removing the N-terminal Aib. The sequence-simplified pentapeptide analogue Phe-Phe-[Aib]-TrpGly-NH2, which was first synthesized and reported by Nachman et al.18 to show resistance to an insect angiotensin converting enzyme and potent diuretic activity, also showed higher aphicidal activity than the K-Aib-1.29 In the present work, we used the structure-simplified pentapeptide analogue Phe-Phe-[Aib]-Trp-Gly-NH2 as the lead compound, and we further incorporated peptidomimetics to this structure, in an attempt to find (a) new analogue(s) with higher activity to employ as (a) new lead(s) for novel eco-insecticide candidates (Figure 1). Three series, comprising 31 analogues, were designed and synthesized by replacing/modifying the positions that played an important role in bioactivities.

thane (DCM) and methanol were purchased from Dima Technology, Inc. (Richmond Hill, Ontario, Canada). Thioanisole, phenol, (substituted) cinnamic acids, phenylacetic acid, hydrocinnamic acid, 4-phenylbutyrilc acid, and 5-phenylpentanoic acid were purchased from Alfa Aesar, U.S.A. General Synthesis Procedure. F[Aib]WG and F[Aib]W[Raa] with Resin was synthesized from Rink Amide-AM resin (536 mg, 0.3 mmol) using the standard Fmoc/tBu chemistry and HBTU/HOBt protocol.30 Incoming amino acids were activated with HOBt (164 mg, 1.2 mmol), HBTU (456 mg, 1.2 mmol), and DIEA (210 μL, 1.2 mmol) in DMF (5 mL) for 5 min, and the couplings were run for 2 h. Removal of the Nterminal Fmoc group from the residues was accomplished with 20% piperidine in DMF (5 mL) for 20 min. The lead compound and analogues were cleaved from the resin with TFA (9 mL) containing 5% phenol, 2.5% thioanisole (0.5 mL), and 5% water (0.5 mL) for 2 h after the mimic acids were coupled to the F[Aib]WG with resin (0.3 mmol) with HOBt (164 mg, 1.2 mmol), HBTU(456 mg, 1.2 mmol), and DIEA (210 μL, 1.2 mmol) in DMF (5 mL) for 3 h at room temperature. Removal of the protective group Boc and tBu was also accomplished in the cleavage procedure. To avoid the generation of OBt esters, some analogues containing a carboxylic acid group were synthesized using Dic as the coupling reagent instead of HBTU/HOBt. The general synthesis procedure is shown in Figure 2. Purification and Characterization. The crude compounds were purified on a C18 reversed-phase semipreparative column with a flow rate of 10 mL/min using different ratio of acetonitrile/water (v/v) from 30/70 to 70/40 containing 0.1% TFA as an ion-pairing reagent. The wavelength of UV detection was set at 214 nm. The purified compounds were run again on HPLC to ensure that the purity was higher than 95%. The structures of the analogues were confirmed by high-resolution mass spectrometry (HRMS) using an Agilent Accurate-MassQ-TOF MS 6520 system equipped with an Electro Spray Ionization (ESI) source. All the MS experiments were detected in the positive ionization mode. For Q-TOF/MS conditions, fragment and capillary voltages were kept at 130 and 3500 V, respectively. Nitrogen was supplied as the nebulizing and drying gas. The temperature of the drying gas was set at 300 °C. The flow rate of the drying gas and the pressure of the nebulizer were 10 L/min and 25 psi, respectively. Full-scan spectra were acquired over a scan range of m/z 80−1200 at 1.03 spectra s−1.

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MATERIALS AND METHODS Synthesis. Materials. Rink Amide-AM resin (0.56 mmol/ g), O-benzotriazole-N,N,N′,N′-tertramethyl uronium hexafluorophosphate (HOBt), 1-hydroxybenzotriazole anhydrate (HBTU), N,N′-diisopropylethylamine (DIEA), N,N′-dissoprophlcarbodiimide (Dic), trifluoroacetic acid (TFA), Fmocprotected amino acids, Fmoc-Gly-OH, Fmoc-N-Me-Gly-OH, Fmoc-L-Phe-OH, Fmoc-L-Trp(Boc)−OH, Fmoc-L-Aib−OH, Fmoc-L-Ala-OH, Fmoc-L-Val-OH, Fmoc-L-Thr-OH, Fmoc-LAsp(OtBu)-OH, Fmoc-L-Asn-OH, Fmoc-Inp-OH, and FmocL-Hyp(tBu)-OH were purchased from GL Biochem, Ltd. (Shanghai, China). High-performance liquid chromatography (HPLC)-grade N,N-dimethylformamide (DMF), dichlorome4528

DOI: 10.1021/acs.jafc.5b01225 J. Agric. Food Chem. 2015, 63, 4527−4532

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Journal of Agricultural and Food Chemistry

analogues, expecting to find (a) new analogue(s) with higher aphicidal activity. As shown in Figure 1, the first step of the strategy is replacing the N-terminal Phe with H, aromatic carboxylic acids with different carbon chain lengths (Series I) and substituted phenyl cinnamic acids (Series II), which have been demonstrated to be good mimics of Phe in our previous work to obtain the optimal mimic of Phe. The result of aphicidal bioassay showed that the optional carbon chain length was 3-C and analogue containing the cinnamic acid group exhibited improved bioactivity. We subsequently used the optimal analogue (II-1) as the second lead, and we performed modifications at the C-terminal Gly, the site shown to enhance inhibition of weight gain and induce significant mortality in Helicoverpa zea larvae when modified with terminal aldehyde or with hydrophilic/hydrophobic natural/unnatural amino acids to assess its importance to bioactivity (Series III). The aphicidal activity against the soybean aphid Aphis glycines of all analogues was evaluated. The analogues were synthesized using the solid-phase peptide synthesis (SPPS) employing the Fmoc protecting group strategy. For avoiding the generation of OBt esters, some analogues containing (substituted) cinnamic acid group were synthesized using Dic as the coupling reagent instead of HBTU/HOBt.37 The purity and high-resolution mass spectrometry (HRMS) data of all target compounds are shown in Table 1. Aphicidal Activity. The aphicidal activity of the lead compound, the analogues, and pymetrozine against A. glycines are shown in Table 1. The preliminary bioassay results (at a concentration of 200 mg/L, 48 h) indicated that all the analogues exhibited aphicidal activity. The aphicidal activity of analogue I-4, I-5, I-6, II-1, II-3, II-10, III-2, III-3, III-6, and III-9 are comparable to or even better than that of the lead compound Phe-Phe-[Aib]-Trp-Gly-NH2. On the basis of the primary experimental results, analogues showing a mortality rate higher than 70% were chosen to determine the LC50 values. As shown in Table 1, I-4, II-1, and III-9 exhibited higher aphicidal activity against soybean aphid with LC50 values of 0.039, 0.019, and 0.034 mmol/L, respectively, compared to the lead compound (LC50 = 0.045 mmol/L). In particular, II-1 was the most toxic compound to the soybean aphid with an LC50 of 0.019 mmol/L, even higher than the commercial insecticide pymetrozine with an LC50 of 0.034 mmol/L. However, the aphicidal activity of analogue II-1 is not statistically significant and still needs to be improved in the further work. Removing the terminal Phe (I-1) significantly decreased the ahpicidal activity, indicating that the N-terminal Phe group was important to maintain the bioactivity of the analogues. Thus, we retained the hydrolysis site Phe, but we modified it with other mimics. Analogues I-4 and II-1, with 3-carbon mimetic aromatic carboxylic acids on the Phe1 position, exhibited higher aphicidal activity than other analogues, suggesting that the optimal carbon chain length of mimetic aromatic carboxylic acids was 3-carbon, whereas the optimal mimic of Phe was the cinnamic acid. We surmised that the CC bond of cinnamic acid might play an important role, such as forming a π−π stacking effect, in the interaction of the mimetic insect kinin analogues with target receptors. Recently, the widely accepted active conformation of an insect kinin C-terminal pentapeptide core region in the interaction of the analogue with the receptor is a 1-4 β-turn. The aromatic side chains of the critical residues Phe1 and Trp4

Figure 2. General synthesis procedure.

Aphicidal Bioassay. The aphicidal activity of the insect kinin analogues against Aphis glycines was determined using the reported procedure.31 Compounds were dissolved to a concentration of 2000 mg/L and then diluted to lower concentrations with 0.05% Triton X100. Soybean leaf discs of about 3 cm diameter were dipped into the test solution for 15 s. The discs dipped into 0.05% Triton X-100 were set as the negative control. After air-drying, the treated leaf discs were placed individually into bioassay plates with 1% agar to keep moist. The discs were infested with 20 ± 3 3-day old aphids and kept in an incubator with constant temperature (25 ± 1 °C) for 48 h. The number of dead aphids was then counted, and the mortality rates were corrected using Abbott’s formula.32 Each experiment was performed three times. The standard deviations of the tested aphicidal values were ≤10%. The LC50 values were calculated using the SAS 9.0 (SAS Institute Inc., U.S.A.).

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RESULTS AND DISCUSSION Design and Synthesis of Analogues. Members of the insect kinin family are inactive in vivo as a consequence of hydrolysis by both hemolymph and tissue-bound peptidases in insects.16,33,34 The two susceptible hydrolytic sites of the kinin core pentapeptide have been reported.10 Analogues with modification and replacement of amino acids at the hydrolysis sites not only showed resistance to peptidases but also retained their bioactivities.7,14,20,27,28 Our previous work demonstrated that the N-terminal Aib of the secondary hydrolysis site of analogue K-Aib-1 did not play an important role in aphicidal activity.29 Removing the N-terminal protective group might not only simplifies the structure but also maintains or even increases the aphicidal activity of analogues. Thus, the simplified analogue Phe-Phe-[Aib]-Trp-Gly-NH2 could be a good lead compound. In this work, we replaced the terminal Phe of the lead compound with different mimics, which was also modified by Nachman et al.35,36 in the N-terminal region of the insect kinin core pentapeptide to discover active diuretic 4529

DOI: 10.1021/acs.jafc.5b01225 J. Agric. Food Chem. 2015, 63, 4527−4532

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Journal of Agricultural and Food Chemistry Table 1. HRMS Results, Purity, and Aphicidal Activity against Aphis glycines of Target Compounds HRMS

aphicidal activity

compd

calcd (m/z)

measured (m/z)

purity (%)

lead I-1 I-2 I-3 I-4 I-5 I-6 II-1 II-2 II-3 II-4 II-5 II-6 II-7 II-8 II-9 II-10 II-11 II-12 II-13 II-14 II-15 III-1 III-2 III-3 III-4 III-5 III-6 III-7 III-8 III-9 III-10 pymetrozine

+

+

98 98 97 98 98 96 98 98 98 97 96 96 96 96 98 98 97 97 98 98 97 96 98 97 99 98 97 98 98 98 99 98 99

[M + H] 640.3242 [M + H]+ 493.2558 [M + H]+ 597.2820 [M + Na]+ 633.2796 [M + Na]+ 647.2952 [M + Na]+ 661.3109 [M + Na]+ 675.3265 [M + Na]+ 645.2796 [M + Na]+ 690.2647 [M + Na]+ 659.2952 [M + Na]+ 679.2406 [M + Na]+ 723.2901 [M + Na]+ 663.2702 [M + H]+ 653.3082 [M + Na]+ 713.2670 [M + Na]+ 679.2406 [M + Na]+ 679.2406 [M + Na]+ 735.2325 [M + Na]+ 687.3265 [M + Na]+ 713.2016 [M + Na]+ 713.2016 [M + Na]+ 713.2016 [M + Na]+ 659.2952 [M + Na]+ 673.3109 [M + Na]+ 659.2952 [M + Na]+ 687.3265 [M + Na]+ 689.3058 [M + H]+ 681.3031 [M + H]+ 680.3191 [M + H]+ 637.3133 [M + H]+ 677.3446 [M + H]+ 679.3239 \

[M + H] 640.3246 [M + H]+ 493.2556 [M + H]+ 597.2819 [M + Na]+ 633.2802 [M + Na]+ 647.2955 [M + Na]+ 661.3101 [M + Na]+ 675.3273 [M + Na]+ 645.2800 [M + Na]+ 690.2649 [M + Na]+ 659.2954 [M + Na]+ 679.2412 [M + Na]+ 723.2982 [M + Na]+ 663.2708 [M + H]+ 653.3079 [M + Na]+ 713.2683 [M + Na]+ 679.2408 [M + Na]+ 679.2403 [M + Na]+ 735.2332 [M + Na]+ 687.3270 [M + Na]+ 713.2019 [M + Na]+ 713.2024 [M + Na]+ 713.2016 [M + Na]+ 659.2955 [M + Na]+ 673.3114 [M + Na]+ 659.2957 [M + Na]+ 687.3261 [M + Na]+ 689.3064 [M + H]+ 681.3028 [M + H]+ 680.3189 [M + H]+ 637.3132 [M + H]+ 677.3450 [M + H]+ 679.3242 \

mortality (%) (200 mg/L,48h)

LC50 (95% FL) (mmol/L, 48 h)

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

0.045 (0.026−0.074) nt nt nt 0.039 (0.032−0.062) 0.170 (0.067−0.22) 0.120 (0.070−0.30) 0.019 (0.0035−0.039) nt 0.140 (0.074−0.44) nt nt nt nt nt nt 0.065 (0.041−0.10) nt nt nt nt nt nt nt nt nt nt nt nt nt 0.034 (0.020−0.063) nt 0.034 (0.012−0.083)

78.56 40.80 54.93 62.56 83.23 73.71 74.93 89.66 58.53 77.04 54.27 56.41 37.98 62.88 37.47 57.56 75.08 50.16 35.03 44.05 36.16 53.67 64.60 68.98 67.16 46.05 63.07 67.18 49.01 63.25 75.99 63.10 90.37

3.04 4.96 2.73 4.24 5.48 2.95 3.94 4.23 4.86 7.16 33.23 4.75 5.00 6.29 2.45 4.62 0.61 5.40 3.43 5.22 4.11 2.64 3.58 7.85 9.87 5.01 7.80 2.75 1.20 3.85 4.67 6.70 2.50

nt: LC50 value was not tested when screening mortality was lower than 70% at the concentration of 200 mg/L, 48 h. 95% FL: 95% fiducial interval.

pymetrozine with an LC50 of 0.034 mmol/L. Therefore, analogue II-1 could be used as a new lead for further chemical modifications and simplifications to discover eco-friendly insecticides.

interact to form a selective aromatic surface that interacts with the receptor site.38 Analogues of series II were designed to determine the substituent effect of the benzene ring of cinnamic acid with different substitutes and they exhibited decreased aphicidal activity to varying degrees compared with II-1. We speculate that substitutions in the benzene ring affected the formation of the aromatic surface and thus interfered with interaction of analogues with the receptor site as a result of their steric stabilization, which led to the decreased bioactivity. Therefore, the side aromatic group without substitution of Phe played a critical role in bioactivity. Further studies on the effect of different side heterocyclic groups without substitution will also be useful to assess. In series III, analogues were designed based on II-1 to assess the importance of the C-terminal Gly. The bioassay result showed that all the analogues were less toxic to the soybean aphid than II-1, which demonstrated that the C-terminal Gly site should be conserved. In summary, three series of novel insect kinin analogues were designed and synthesized. The aphicidal bioassay results showed that most analogues exhibited considerable aphicidal activity against A. glycines, especially analogue II-1 with an LC50 of 0.019 mmol/L, which exhibited improved aphicidal activity compared with the lead compound (LC50 = 0.045 mmol/L), and comparable activity to the commercial insecticide

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel: +86-10-62732223. Author Contributions

C.-L.Z., Y.L., and X.-L.Y. designed the analogues and experiments. C.-L.Z. and X.-Q.W. performed the synthesis and purification of analogues. C.-L.Z., Y.-Y.Q., and D.-L.S. conducted the aphicidal bioassay. C.-L.Z., D.-L.S., Y.L., and X.L.Y. analyzed the data. C.-L.Z. and X.-L.Y. wrote the manuscript. All authors read and approved the final manuscript. Funding

This study was financially supported by the National Natural Science Foundation of China (No. 21132003) and the National “Twelfth Five-Year” Plan for Science and Technology (No. 2011BAE06B05-5). Notes

The authors declare no competing financial interest. 4530

DOI: 10.1021/acs.jafc.5b01225 J. Agric. Food Chem. 2015, 63, 4527−4532

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Journal of Agricultural and Food Chemistry

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ACKNOWLEDGMENTS We are grateful to Professor Stephen Tobe and Dr. Juan Huang for their kind help on this manuscript writing.

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DOI: 10.1021/acs.jafc.5b01225 J. Agric. Food Chem. 2015, 63, 4527−4532

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DOI: 10.1021/acs.jafc.5b01225 J. Agric. Food Chem. 2015, 63, 4527−4532