Abstract
This review describes the development of a new integrated approach to the generation of a novel type of insect neuropeptide (Np) antagonists and putative insect control agents based on conformationally constrained compounds. The new approach, termed insect Np-based antagonist insecticide (INAI), was applied to the insect pyrokinin (PK)/pheromone biosynthesis-activating Np (PBAN) family as a model and led to the discovery of a potent linear lead antagonist and several highly potent, metabolically stable backbone cyclic (BBC) conformationally constrained antagonists that were devoid of agonistic activity and inhibited sex pheromone biosynthesis in female moths in vivo. This review summarizes the above approach, briefly describes the PK/PBAN Np family, presents data on the in vivo activity of the antagonists, summarizes data on the PK/PBAN receptor, and introduces the advantages of this method for generation of Np antagonists as a basis for the design of insect control agents.
Similar content being viewed by others
References
Abernathy, R. L., Nachman, R. J., Teal, P. E. A., Yamashita, O., and Tumlinson, J. H. (1995) Pheromonotropic activity of naturally occurring pyrokinin insect neuropeptides (FXPRLamide) in Helicoverpa zea. Peptides 16, 215–219.
Altstein, M. (2001) Insect neuropeptide antagonists. Biopolymers (Pept. Sci.) 60, 460–473.
Altstein, M., Ben-Aziz, O., Bhargava, K., Li Q., and Martins-Green, M. (2003) Histochemical localization of the PBAN receptor in the pheromone gland of Heliothis peltigera. Peptides 24, 1335–1347.
Altstein, M., Ben-Aziz, O., Daniel, S., Schefler, I., Zeltser, I., and Gilon, C. (1999a) Backbone cyclic peptide antagonists, derived from the insect pheromone biosynthesis activating neuropeptide (PBAN), inhibit sex pheromone biosynthesis in moths. J. Biol. Chem. 274, 17573–17579.
Altstein, M., Ben-Aziz, O., Daniel, S., Zeltser, I., and Gilon, C. (2001) Pyrokinin/PBAN radio-receptor assay: development and application for the characterization of a putative receptor from the pheromone gland of Heliothis peltigera. Peptides 22, 1379–1389.
Altstein, M., Ben-Aziz, O., Gabay, T., Gazit, Y., and Dunkelblum, E. (1996a) Structure-function relationship of PBAN/MRCH, in Insect Pheromone Research: New Directions, Carde, R. T., and Minks, A. K., eds. Chapman and Hall, New York, pp. 56–63.
Altstein, M., Ben-Aziz, O., Schefler, I., Zeltser, I., and Gilon, C. (2000). Advances in the application of neuropeptides in insect control. Crop Prot. 19, 547–555.
Altstein, M., Dunkelblum, E., Gabay, T., Ben-Aziz, O., Schafler, I., and Gazit, Y. (1995) PBAN-induced sex pheromone biosynthesis in Heliothis peltigera: Structure, dose and time-dependent analysis. Arch. Insect Biochem. Physiol. 30, 309–317.
Altstein, M., Dunkelblum, E., Gazit, Y., Ben Aziz, O., Gabay, T., Vogel, Z., and Barg, J. (1997) Structure-function analysis of PBAN/MRCH: A basis for antagonist design, in Modern Agriculture and the Environment, Rosen D. et al., eds., Kluwer Academic Publishers, Dordrecht, The Netherlands, pp. 109–116.
Altstein, M., Gabay, T., Ben Aziz, O., Daniel, S., Zeltser, I., and Gilon, C. (1999b) Characterization of the pheromone biosynthesis activation neuropeptide (PBAN) receptor from the pheromone gland of Heliothis peltigera. Invertebrate Neurosci. 4, 33–40.
Altstein, M., Gazit, Y., Ben Aziz, O., Gabay, T., Marcus, R., Vogel, Z., and Barg, J. (1996b) Induction of cuticular melanization in Spodoptera littoralis larvae by PBAN/MRCH: Development of a quantitative bioassay and structure function analysis. Arch. Insect Biochem. Physiol. 31, 355–370.
Becker, J. A. J., Wallace, A., Garzon, A., Ingallinella, P., Bianchi, E., Cortese, R., et al. (1999) Ligands for κ-opioid and ORL1 receptors identified from a conformationally constrained peptide combinatorial library. J. Biol. Chem. 274, 27513–27522.
Choi, M. Y., Tanaka, M., Kataoka, H., Boo, K. S., and Tatsuki, S. (1998) Isolation and identification of the cDNA encoding the pheromone biosynthesis activating neuropeptide and additional neuropeptides in the oriental tobacco budworm, Helicoverpa assulta (Lepidoptera: Noctuidae). Insect Biochem. Mol. Biol. 28, 759–766.
Cody, W. L., He, J. X., DePue, P. L., Waite, L. A., Leonard, D. M., Sefler, A. M., et al. (1995) Structure-activity relationships of the potent combined endothelin-A/endothelin-B receptor antagonist Ac-DDip16-Leu-Asp-Ile-Ile-Trp21: development of endothelin-B receptor selective antagonists. J. Med. Chem. 21, 2809–2819.
Collins, N., Flippen-Anderson, J. L., Haaseth, R. C., Deschamps, J. R., George, C., Kövér, K., and Hruby, V. J. (1996) Conformational determinants of agonist versus antagonist properties of [d-Pen2, d-Pen5]enkephalin (DPDPE) analogs at opioid receptors. Comparison of X-ray crystallographic structure, solution 1HNMR data and molecular dynamic simulations of [l-Ala3] DPDPE and [δ-Ala3]DPDPE. J. Am. Chem. Soc. 118, 2143–2152.
Coy, D. H., Heinz-Erian, P., Jiang, N.-Y., Sasaki, J., Taylor, J., Moreau, J.-P., et al. (1988) A novel bombesin antagonist with reduced peptide bond. J. Biol. Chem. 263, 5055–5060.
Coy, D. H., Taylor, J., Jiang, N.- Y., Kim, S. H., Wang, L.-H., Huang, S. C., et al. (1989) Short chain bombesin receptor antagonists with IC50s for cellular secretion and growth approaching the picomolar region. Peptides 11, pp. 65–67.
Davis, M.-T. B., Vakharia, V. N., Henry, J., Kempe, T. G., and Raina, A. K. (1992) Molecular cloning of the pheromone biosynthesis-activating neuropeptide in Helicoverpa zea. Proc. Natl. Acad. Sci. USA 89, 142–146.
Devlin, J. P. (1997) High Throughput Screening: The Discovery of Bioactive Substances, Marcel Dekker, New York.
Duportets, L., Gadenne, C., Dufour, M. C., and Couillaud, F. (1998) The pheromone biosynthesis activating neuropeptide (PBAN) of the black cutworm moth, Agrotis ipsilon: immunohistochemistry, molecular characterization and bioassay of its peptide sequence. Insect Biochem. Mol. Biol. 28, 591–599.
Folkers, K., Jakanson, R., Horig, J., Xu, J. C., and Leander, S. (1984) Biological evaluation of substance P antagonists. Br. J. Pharmacol. 83, 449–456.
Fónagy, A., Schoofs, L., Matsumotor, S., De Loof, A., and Mitsui, T. M. (1992) Functional cross-reactivity of some locustamyotropins and Bombyx pheromone biosynthesis activating neuropeptide. J. Insect Physiol. 38, 651–657.
Gäde, G. (1997) The explosion of structural information on insect neuropeptides. Prog. Chem. Org. Nat. Prod. 71, 1–128.
Gazit, Y., Dunkelblum, E., Benichis M., and Altstein, M. (1990) Effect of synthetic PBAN and derived peptides on sex pheromone biosynthesis in Heliothis peltigera (Lepidoptera: Noctuidae). Insect Biochem. 20, 853–858.
Gilon, C., Halle, D., Chorev, M., Selinger, Z., and Byk, G. (1991) Backbone cyclization: A new method for conferring conformational constraint on peptides. Biopolymers 31, 745–750.
Gilon, C., Huonges, M., Matha, B., Gellerman, G., Hornik, V., Rosenfeld, R., et al. (1998a) Abackbone-cyclic, receptor 5-selective somatostatin analogue: synthesis, bioactivity, and nuclear magnetic resonance conformational analysis. J. Med. Chem. 41, 919–929.
Gilon, C., Muller, D., Bitan, G., Salitra, Y., Goldwasser, I., and Hornik, V. (1998b) Cycloscan: conformational libraries of backbone cyclic peptides, in Peptides Chemistry, Structure and Biology, Ramage, R., and Epton, R., eds., Mayflower Scientific, England, pp. 423–424.
Gilon, C., Zeltser, I., Daniel, S., Ben-Aziz, O., Schefler, I., and Altstein, M. (1997) Rationally designed neuropeptide antagonists: a novel approach for generation of environmentally friendly insecticides. Invertebrate Neurosci. 3, 245–250.
Golic-Gradadolnik, S., Mierke, D. F., Byk, G., Zeltser, I., Gilon, C., and Kessleer, H. (1994) Comparison of the conformations of active and nonactive backbone cyclic analogs of substance P as a tool to elucidate features of the bioactive conformation: NMR and molecular dynamics in water and dimethylsulfoxide. J. Med. Chem. 37, 2145–2152.
Goodman, M. and Ro, S. (1995) Peptidomimetics for drug design, in Medicinal Chemistry and Drug Discovery, 5th ed., Vol. 1, Wolff, E., ed., John Wiley, New York, pp. 803–861.
Heinz-Erian, P., Coy, D. H., Tamura, M., Jones, S. W., Gardener, J. D. and Jensen, R. T. (1987) [D-Phe12]bombesin analogues: a new class of bombesin receptor antagonists. Am. J. Physiol. 252, G439-G442.
Holman, G. M., Nachman, R. J., Schoofs, L., Hayes, T. K., Wright, M. S., and DeLoof, A. (1991) The Leucophaea hindgut preparation is a rapid and sensitive bioassay tool for the isolation of insect myotropins of other insect species. Insect Biochem. 21, 107–112.
Hruby, V.J. (1981a) Structural and conformation analyses related to the activity of peptide hormones, in Perspectives in Peptide Chemistry, Eberle, A., Geiger, R., and Weiland, T., eds., S. Karger, Basel, Switzerland, pp. 207–220.
Hruby, V. J. (1981b) Relation of conformation to biological activity in oxytocin, vasopressin and their analogues, in Topics in Molecular Pharmacology, Vol. 1, Burgen S. V., and Roberts G. C. K., eds., Elsevier, Amsterdam, The Netherlands, pp. 99–126.
Hruby, V. J. (1992) Strategies in the development of peptide antagonists. Prog. Brain Res. 92, 215–224.
Hruby, V. J., Al-Obeidi, F., and Kazmierski, W. (1990) Emerging approaches in the molecular design of receptor-selective peptide ligands: conformational, topographical and dynamic considerations. Biochem. J. 268, 249–262.
Iglesias, F., Marco, P., Francois, M.-C., Camps, F., Fabrias, G., and Jacquim-Joly, E. (2002). A new member of the PBAN family in Spodoptera littoralis: molecular cloning and immuno-visualisation in scotophase hemolymph. Insect Biochem. Mol. Biol. 32, 901–908.
Imai, K., Konno, T., Nakazawa, Y., Komiya, T., Isobe, M., Koga, K., et al. (1991) Isolation and structure of diapause hormone of the silkworm, Bombyx mori. Proc. Japan Acad. 67, 98–101.
Jacquin-Joly, E., Burnet, M., Franxois, M. C., Ammar, D., Nagnan-Le, Meillour, P., and Descoins, C. (1998) cDNA cloning and sequence determination of the pheromone biosynthesis activating neuropeptide of Mamestra brassicae: a new member of the PBAN family. Insect Biochem. Mol. Biol. 28, 251–258.
Kasher, R., Oren, D. S., Barda, Y., and Gilon, C. (1999) Protein miniaturization: the backbone cyclic proteinomimetic approach. J. Mol. Biol. 292, 421–429.
Kawano, T., Kataoka, H., Nagasawa, H., Isogai, A., and Suzuki, A. (1992) cDNA cloning and sequence determination of the pheromone biosynthesis activating neuropeptide of the silkworm, Bombyx mori. Biochem. Biophys. Res. Comm. 189, 221–226.
Kawano, T., Kataoka, H., Nagasawa, H., Isogai, A., and Suzuki, A. (1997) Molecular cloning of a new type of c-DNA for pheromone biosynthesis activating neuropeptide in the silkworm, Bombyx mori. Biosci. Biotech. Biochem. 61, 1745–1747.
Kessler, H. (1982) Conformation and biological activity of cyclic peptides. Angew. Chem. Int. Ed. Engl. 21, 512–523.
Kitamura, A., Nagasawa, H., Kataoka, H., Ando, T., and Suzuki, A. (1990) Amino acid sequence of pheromone biosynthesis activating neuropeptide-II (PBAN-II) of the silkmoth Bombyx mori. Agric. Biol. Chem. 54, 2495–2497.
Kitamura, A., Nagasawa, H., Kataoka, H., Inoue, T., Matsumoto, S., Ando, T., and Suzuki, A. (1989) Amino acid sequence of pheromone-biosynthesis-activating neuropeptide (PBAN) of the silkworm Bombyx mori. Biochem. Biophys. Res. Commun. 163, 520–526.
Kochansky, J. P., Raina, A. K., and Kempe, T. G. (1997) Structure-activity relationship in C-terminal fragment analogs of pheromone biosynthesis activating neuropeptide in Helicoverpa zea. Arch. Insect. Biochem. Physiol. 35, 315–332.
Kuniyoshi, H., Nagasawa, H., Ando, T., and Suzuki, A. (1992a) N-terminal modified analogs of C-terminal fragments of PBAN with pheromonotropic activity. Insect Biochem. Mol. Biol. 22, 399–403.
Kuniyoshi, H., Nagasawa, H., Ando, T., Suzuki, A., Nachman, R. J., and Holman, M.G. (1992b) Cross-activity between pheromone biosynthesis activating neuropeptide (PBAN) and myotropic pyrokinin insect peptides. Biosci. Biotechnol. 56, 167–168.
Llinares, M., Devin, C., Chloin, O., Azay, J., Noel-Artis, A.-M., Bernad, N., Fehrentz, J.-A., and Martinez J. (1999) Synthesis and biological activities of potent bombesin receptor antagonists. J. Pept. Res. 53, 275–283.
Ma, P. W. K., Knipple, D. C., and Roelofs, W. L. (1994) Structural organization of the Helicoverpa zea gene encoding the precursor protein for pheromone biosynthesis-activating neuropeptide and other neuropeptides. Proc. Natl. Acad. Sci. USA 91, 6506–6510.
Maretto, S., Schievano, E., Mammi, S., Bisello, A., Nakamoto, C., Rosenblatt, M., et al. (1998) Conformational studies of a potent Leu11, D-Trp12-containing lactam-bridged parathyroid hormone-related protein-derived antagonist. J. Pept. Res. 52, 241–248.
Masler, E. P., Raina, A. K., Wagner, R. M., and Kochansky, J. P. (1994) Isolation and identification of a pheromonotropic neuropeptide from the brain-suboesophageal ganglion complex of Lymantria dispar: new member of the PBAN family. J. Insect Biochem. Mol. Biol. 24, 829–836.
Matsumoto, S., Fónagy, A., Kurihara, M., Uchiumi, K., Nagamine, T., Chijimatsu, M., and Mitsui, T. (1992) Isolation and primary structure of a novel pheromonotropic neuropeptide structurally related to leucopyrokinin from the armyworm larvae, Pseudaletia separata. Biochem. Biophys. Res. Commun. 182, 534–539.
Matsumoto, S., Kitamura, A., Nagasawa, H., Kataoka, H., Orikasa, C., Mitsui, T., and Suzuki, A. (1990) Functional diversity of a neurohormone produced by the suboesophageal ganglion: molecular identity of melanization and reddish colouration hormone and pheromone biosynthesis activating neuropeptide. J. Insect Physiol. 36, 427–432.
Nachman, R. J., Holman, M. G., and Cook, B. J. (1986) Active fragments and analogs of the insect neuropeptide leucopyrokinin: structure-function studies. Biochem. Biophys. Res. Commun. 137, 936–942.
Nachman, R.J., Kuniyoshi, H., Roberts, V. A., Holman, G. M., and Suzuki, A. (1993a) Active conformation of the pyrokinin/PBAN neuropeptide family for pheromone biosynthesis in the silkworm. Biochem. Biophys. Res. Commun. 193, 661–666.
Nachman, R. J., Holman, M. G. and Haddon, W. F. (1993b) Leads for insect neuropeptide mimetic development. Arch. Insect. Biochem. Physiol. 22, 181–197.
Nachman, R. J., Holman, G. M., Schoofs, L., and Yamashita, O. (1993c) Silkworm diapause induction activity of myotropic pyrokinin (FXPRLamide) insect Nps. Peptides 14, 1043–1048.
Nachman, R. J., Zdareej, J., Holman, M. G., and Hayes, T. K. (1997) Pupariation acceleration in fleshfly (Sarcophaga bullata) larvae by the pyrokinin/PBAN neuropeptide family. Ann. N. Y. Acad. Sci. 814, 73–79.
Nagasawa, H., Kuniyoshi, H., Arima, R., Kawano, T., Ando, T., and Suzuki, A. (1994) Structure and activity of Bombyx PBAN. Arch. Insect Biochem. Physiol. 25, 261–270.
Nässel, D. R. (2002) Neuropeptides in the nervous system of Drosophila and other insects: multiple roles as neuromodulators and neurohormones. Prog. Neurobiol. 68, 1–84.
Piercey, M. F., Schroeder, L. A., and Einspahr, F. J. (1981) Behavioral evidence that substance P may be a spinal cord nociceptor neurotransmitter, in Peptides: Synthesis-Structure-Function, Rich, D. H., and Gross, E., eds., Pierce Chemical Co., Rockford, IL, pp. 589–592.
Poyner, D., Cox, H., Bushfield, M., Treherne, J. M., and Demetrikpopulos, M. K. (2000) Neuropeptides in drug research. Prog. Drug Res. 54, 121–149.
Rafaeli, A. (2002) Neuroendocrine control of pheromone biosynthesis in moths. Int. Rev. Cytol. 213, 49–91.
Raina, A. K. and Klun, J. A. (1984) Brain factor control of sex pheromone production in the female corn earworm moth. Science 225, 531–533.
Raina, A. K. and Gäde, G. (1988) Insect peptide nomenclature. Insect Biochem. 18, 785–787.
Raina, A. K., Jaffe, H., Kempe, T. G., Keim, P., Blacher, R. W., Fales, H. M., et al. (1989) Identification of a neuropeptide hormone that regulates sex pheromone production in female moths. Science 244, 796–798.
Raina, A. K. and Kempe, T. G. (1990) A pentapeptide of the C-terminal sequence of PBAN with pheromonotropic activity. Insect Biochem. 20, 849–851.
Raina, A. K. and Kempe, T. G. (1992) Structure activity studies of PBAN of Helicoverpa zea (Lepidoptera: Noctuidae). Insect Biochem. Mol. Biol. 22, 221–225.
Rees, R. W. A., Foell, T. J., Chai, S.-Y., and Grant, N. (1974) Synthesis and biological activities of analogues of the luteinizing hormone-releasing hormone (LH-RH)modified in position 2. J. Med. Chem. 17, 1016–1019.
Rhaleb, N.-E., Télémaque, S., Roussi, N., Dion, S., Jukic, D., Drapeau, G., and Regoli, D. (1991) Structure-activity studies of bradykinin and related peptides. Hypertension 17, 107–115.
Rodriguez, M., Dubreuil, P., Laur, J., Bali, J. P., and Martinez, J. (1987) Synthesis and biological activity of partially modified retro-inverso pseudopeptide derivatives of the C-terminal tetrapeptide of gastrin. J. Med. Chem. 30, 758–763.
Rosell, S., Björkroth, U., Xu, J. C., and Folkers, K. (1983) The pharmacological profile of a substance P (SP) antagonists. Evidence for the existence of subpopulations of SP receptors. Acta Physiol. Scand. 117, 445–449.
Saulitis, J., Mierke, D. F., Byk, G., Gilon, C., and Kessler, H. (1992) Conformation of cyclic analogous of substance P: NMR and molecular dynamics in dimethylsulfoxide. J. Am. Chem. Soc. 114, 4818–4823.
Sawyer, W. H., Pang, P. K. T., Seto, J., and McEnroe, M. (1981) Vasopressin analogs that antagonize antidiuretic responses by rats to the antidiuretic hormone. Science 212, 4951–4953.
Schoofs, L., Holman, M. G., Nachman, R. J., Hayes, T. K., and DeLoof, A. (1991) Isolation, primary structure, and synthesis of locustapyrokinin: a myotropic peptide of Locusta migratoria. Gen. Comp. Endocrinol. 81, 97–104.
Schoofs, L., Vanden, J. B., and De Loof, A. (1993) The myotropic peptides of Locusta migratoria: Structures, distribution, functions and receptors. Insect Biochem. Mol. Biol. 23, 859–881.
Teal, P. E. A., Abernathy, R. L., Nachman, R. J., Fang, N., Meredith, J. A., and Tumlinson, J. H. (1996) Pheromone biosynthesis activating neuropeptides: functions and chemistry. Peptides 17, 337–344.
Vale, W., Grant, G., Rivier, J. E., Monahan, M., Amoss, M., Blackwell, R., et al. (1972) Synthetic polypeptide antagonists of the hypothalamic luteinizing hormone releasing hormone. Science 176, 933–934.
Vevrek, R. J. and Stewart, J. M. (1985) Competitive antagonists of bradykinin. Peptides 6, 161–164.
Zdarek, J., Nachman, R. J., and Hayes, T. K. (1998) Structure-activity relationships of insect Nps of the pyrokinin/PBAN family and their selective action on pupariation in fleshfly (Neobelleria bullata) larvae. Eur. J. Entomol. 95, 9–16.
Zeltser, I. Gilon, G., Ben-Aziz, O., Schefler, I., and Altstein, M. (2000) Discovery of a linear lead antagonist to the insect pheromone biosynthesis activating neuropeptide (PBAN). Peptides 21, 1457–1467.
Zeltser, I. Ben-Aziz, O., Schefler, I. Bhargava, K., Altstein, M., and Gilon, C. (2001) Insect neuropeptide antagonists Part II: Synthesis and biological activity of backbone cyclic and precyclic PBAN antagonists. J. Pept. Res. 58, 1–13.
Author information
Authors and Affiliations
Corresponding author
Additional information
Contribution from the Agricultural Research Organization, the Volcani Center, Bet Dagan, Israel. No. 516/03, 2003 series.
Rights and permissions
About this article
Cite this article
Altstein, M. Novel insect control agents based on neuropeptide antagonists. J Mol Neurosci 22, 147–157 (2004). https://doi.org/10.1385/JMN:22:1-2:147
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1385/JMN:22:1-2:147