Interaction of Mimetic Analogs of Insect Kinin Neuropeptides with Arthropod Receptors

  • Ronald J. NachmanEmail author
  • Patricia V. Pietrantonio
Part of the Advances in Experimental Medicine and Biology book series (volume 692)


Insect kinin neuropeptides share a common C-terminal pentapeptide sequence Phe1-Xaa1 2-Xaa2 3-Trp4-Gly5-NH2 (Xaa1 2?His, Asn, Phe, Ser or Tyr; Xaa2 3?Pro, Ser or Ala) and have been isolated from a number of insects, including species of Dictyoptera, Orthoptera and Lepidoptera. They have been associated with the regulation of such diverse processes as hindgut contraction, diuresis and the release of digestive enzymes. In this chapter, the chemical, conformational and stereochemical aspects of the activity of the insect kinins with expressed receptors and/or biological assays are reviewed. With this information, biostable analogs are designed that protect peptidase-susceptible sites in the insect kinin sequence and demonstrate significant retention of activity on both receptor and biological assays. The identification of the most critical residue of the insect kinins for receptor interaction is used to select a scaffold for a recombinant library that leads to identification of a nonpeptide mimetic analog. C-terminal aldehyde insect kinin analogs modify the activity of the insect kinins leading to inhibition of weight gain and mortality in corn earworm larvae and selective inhibition of diuresis in the housefly. Strategies for the modification of insect neuropeptide structures for the enhancement of the topical and oral bioavailability of insect neuropeptides and the promotion of time-release from the cuticle and/or foregut are reviewed. Promising mimetic analog leads for the development of selective agents capable of disrupting insect kinin regulated processes are identified that may provide interesting tools for arthropod endocrinologists and new pest insect management strategies in the future.


Malpighian Tubule Kinin Receptor Pheromone Production Diuretic Activity Secretion Assay 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Holman GM, Cook BJ, Nachman RJ. Isolation, primary structure and synthesis of Leucokinins VII and VIII: The final members of this new family of chephalomyotropic peptides isolated from head extracts of Leucophaea maderae. Comp Biochem Physiol 1987; 88C(1):31–4.Google Scholar
  2. 2.
    Coast GM. The regulation of primary urine production in insects. In: Coast GM, Webster SG, eds. Recent Advances in Arthropod Endocrinology. Cambridge: Cambridge University Press, 1998:189–209.Google Scholar
  3. 3.
    Nachman RJ, Strey A, Isaac E et al. Enhanced in vivo activity of peptidase-resistant analogs of the insect kinin neuropeptide family. Peptides 2002a; 23:735–45.CrossRefPubMedGoogle Scholar
  4. 4.
    Coast GM, Holman GM, Nachman RJ. The diuretic activity of a series of cephalomyotropic neuropeptides, the achetakinins, on isolated malpighian tubules of the house cricket, Acheta domesticus. J Insect Physiol 1990; 36(7):481–8.CrossRefGoogle Scholar
  5. 5.
    Nachman RJ, Holman GM. Myotropic insect neuropeptide families from the cockroach Leucophaea maderae: Structure-activity relationships. In: Menn JJ, Masler EP, eds. Insect Neuropeptides: Chemistry, Biology and Action. Washington, DC: American Chemical Society, 1991:194–214.CrossRefGoogle Scholar
  6. 6.
    Sajjaya P, Deepa Chandran S, Sreekumar S et al. In vitro regulation of gut pH by neuropeptide analogues in the larvae of red palm weevil, Rhynchophorus ferrugineus. J Adv Zool 2001; 22(1):26–30.Google Scholar
  7. 7.
    Harshini S, Nachman RJ, Sreekumar S. Inhibition of digestive enzyme release by neuropeptides in larvae of Opisina arenosella (Lepidoptera: Cryptophasidae). Comp Biochem Physiol 2002; B132:353–8.Google Scholar
  8. 8.
    Harshini S, Manchu V, Sunitha VB et al. In vitro release of amylase by culekinins in two insects: Opisinia arenosella (Lepidoptera) and Rhynchophorus ferrugineus (Coleoptera). Trends Life Sci 2003; 17:61–4.Google Scholar
  9. 9.
    Seinsche A, Dyker H, Losel P et al. Effect of helicokinins and ACE inhibitors on water balance and development of Heliothis virescens larvae. J Insect Physiol 2000; 46:1423–31.CrossRefPubMedGoogle Scholar
  10. 10.
    Nachman RJ, Isaac RE, Coast GM et al. Aib-containing analogues of the insect kinin neuropeptide family demonstrate resistance to an insect angiotensin-converting enzyme and potent diuretic activity. Peptides 1997; 18:53–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Nachman RJ, Roberts VA, Holman GM et al. Concensus chemistry and conformation of an insect neuropeptide family analogous to the tachykinins. In: Epple A, Scanes CG, Stetson MH, eds. Progress in Comparative Endocrinology. New York: Wiley-Liss, Inc, 1990:342:60–6.Google Scholar
  12. 12.
    Cornell MJ, Williams TA, Lamango NS et al. Cloning and expression of an evolutionary conserved single-domain angiotensin converting enzyme from Drosophila melanogaster. J Biol Chem 1995; 270:13613–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Lamango NS, Sajid M, Isaac RE. The endopeptidase activity and the activation by Cl?of angiotensin-converting enzyme is evolutionarily conserved: purification and properties of an antiotensin-converting enzyme from the housefly, Musca domestica Nazarius. Biochem J 1996; 314:639–46.PubMedGoogle Scholar
  14. 14.
    King FD, Wilson S. Recent advances in 7-transmembrane receptor research. Curent Opin Drug discovery Development 1999; 2:83–95.Google Scholar
  15. 15.
    Von Zastrow M. Mechanisms regulating membrane trafficking of G protein-coupled receptors in the endocytic pathway. Life Sci 2003; 74:217–24.CrossRefGoogle Scholar
  16. 16.
    Marchese A, Chen C, Kim YM et al. The ins and outs of G protein-coupled receptor trafficking. Trends Biochem Sci 2003; 8:369–76.CrossRefGoogle Scholar
  17. 17.
    Bondensgaard K, Ankersen M, Thogersen H et al. Recognition of privileged structures by G-protein coupled receptors. J Med Chem 2004; 47:888–99.CrossRefPubMedGoogle Scholar
  18. 18.
    Vanden Broeck J. Insect G protein-coupled receptors and signal transduction. Arch Insect Biochem Physiol 2001; 48:1–12.CrossRefPubMedGoogle Scholar
  19. 19.
    Holmes SP, He H, Chen AC et al. Cloning and transcriptional expression of a leucokinin-like peptide receptor from the southern cattle tick, Boophilus microplus (Acari: Ixodidae). Insect Mol Biol 2000; 9:457–65.CrossRefPubMedGoogle Scholar
  20. 20.
    Cox KJA, Tensen CP, Van der Schors RC et al. Cloning, characterization and expression of a G-protein-coupled receptor from Lymnaea stagnalis and identification of a leucokinin-like peptide, PSFHSWSamide, as its endogenous ligand. J Neurosci 1997; 17:1197–205.PubMedGoogle Scholar
  21. 21.
    Holmes SP, Barhoumi R, Nachman RJ et al. Functional analysis of a G protein-coupled receptor from the southern cattle tick Boophilus microplus (Acari: Ixodidae) identifies it as the first arthropod myokinin receptor. Insect Mol Biol 2003; 12:27–38.CrossRefPubMedGoogle Scholar
  22. 22.
    Radford JC, Davies SA, Dow JAT. Systematic G-protein-coupled receptor analysis in Drosophila melanogaster identifies a leucokinin receptor with novel roles. J Biol Chem 2002; 277:38810–7.CrossRefPubMedGoogle Scholar
  23. 23.
    Hayes TK, Pannabecker TL, Hincley DJ et al. Leucokinins, a new family of ion transport stimulators and inhibitors in insect Malpighian tubules. Life Sci 1989; 44(18):1259–66.CrossRefPubMedGoogle Scholar
  24. 24.
    Veenstra JA, Pattillo JM, Petzel DH. A single cDNA encodes all three Aedes leucokinins, which stimulate both fluid secretion by the Malpighian tubules and hindgut contractions. J Biol Chem 1997; 272(16):10402–7.CrossRefPubMedGoogle Scholar
  25. 25.
    Pietrantonio PV, Jagge C, Taneja-Bageshwar S et al. The mosquito Aedes aegypti (L.) leucokinin receptor is a multiligand receptor for the three Aedes kinins. Insect Mol Biol 2005; 14(1):55–67.CrossRefPubMedGoogle Scholar
  26. 26.
    Wang J. Kean L. Yang J et al. Function-informed transcriptome analysis of Drosophila renal tubule. Genome Biol 2004; 5(9):R69. Epub 2004.CrossRefPubMedGoogle Scholar
  27. 27.
    Coast GM. Fluid secretion by single isolated Malpighian tubules of the house cricket, Acheta domesticus and their response to diuretic hormone. Physiol Entomol 1988; 13:381–91.CrossRefGoogle Scholar
  28. 28.
    O’Donnell MJ, Rheault MR, Davies SA et al. Hormonally controlled chloride movements across Drosophila tubules is via ion channels in stellate cells. Am J Physiol 1998; 274 (Regulatory Integrative Comp Physiol 43): R1039–49.PubMedGoogle Scholar
  29. 29.
    Wang S, Rubenfeld AB, Hayes TK et al. Leucokinin increases paracellular permeability in insect Malpighian tubules. J Exp Biol 1996; 199:2537–42.PubMedGoogle Scholar
  30. 30.
    Kim Y-J, Žitňan D, Galizia CG et al. A command chemical triggers an innate behavior by sequential activation of multiple peptidergic ensembles. Curr Biol 2006a; 16:1395–407.CrossRefPubMedGoogle Scholar
  31. 31.
    Kim Y-J, Žitňan D, Cho K-H et al. Central peptidergic ensembles associated with organization of an innate behavior. Proc Natl Acad Sci USA 2006b; 103(38):14211–6.CrossRefGoogle Scholar
  32. 32.
    Li B, Predel R, Neupert S et al. Genomics, transcriptomics and peptidomics of peptide and protein hormones in the red flour beetle Tribolium castaneum. Genome Res 2008; 18(1):113–22.CrossRefPubMedGoogle Scholar
  33. 33.
    Nachman RJ, Roberts VA, Holman GM et al. Leads for insect neuropeptide mimetic development. Arch. Insect Biochem Physiol 1993; 22:181–97.CrossRefPubMedGoogle Scholar
  34. 34.
    Nachman RJ, Coast GM, Douat C et al. A C-terminal aldehyde insect kinin analog enhances inhibition of weight gain and induces significant mortality in Helicoverpa zea larvae. Peptides 2003; 24:1615–21.CrossRefPubMedGoogle Scholar
  35. 35.
    Coast GM, Zabrocki J, Nachman RJ. Diuretic and myotropic activities of N-terminal truncated analogs of Musca domestica kinin neuropeptide. Peptides 2002; 23:701–8.CrossRefPubMedGoogle Scholar
  36. 36.
    Nachman RJ, Coast GM, Holman GM et al. Diuretic activity of C-terminal group analogues of the insect kinins in Acheta domesticus. Peptides 1995; 16:809–13.CrossRefPubMedGoogle Scholar
  37. 37.
    Taneja-Bageshwar S, Strey A, Zubrzak P et al. Comparative structure-activity analysis of insect kinin core analogs on recombinant kinin receptors from Southern cattle tick Boophilus microplus (Acari: Ixodidae) and mosquito Aedes aegypti (Diptera: Culicidae). Arch Insect Biochem Physiol 2006; 62(3):128–40.CrossRefPubMedGoogle Scholar
  38. 38.
    Moyna G, Williams HJ, Nachman RJ et al. Conformation in solution and dynamics of a structurally constrained linear insect kinin pentapeptide analogue. Biopolymers 1999; 49:403–13.CrossRefPubMedGoogle Scholar
  39. 39.
    Roberts VA, Nachman RJ, Coast GM et al. Consensus chemistry and beta-turn conformation of the active core of the insect kinin neuropeptide family. Chem Biol 1997; 4:105–17.CrossRefPubMedGoogle Scholar
  40. 40.
    Nachman RJ, Zabrocki J, Olczak J et al. cis-Peptide bond mimetic tetrazole analogs of the insect kinins identify the active conformation. Peptides 2002c; 23:709–16.CrossRefPubMedGoogle Scholar
  41. 41.
    Nachman RJ, Kaczmarek K, Williams HJ et al. An active insect kinin analog with 4-aminopyroglutamate, a novel cis-peptide bond, type VI β-turn motif. Bioploymers 2004; 75:412–19.CrossRefGoogle Scholar
  42. 42.
    Kaczmarek K, Williams HJ, Coast GM et al. Comparison of insect kinin analogs with cis-peptide bond motif 4-aminopyroglutamate identifies optimal stereochemistry for diuretic activity. Biopolymers (Peptide Sci) 2007; 88:1–7.CrossRefGoogle Scholar
  43. 43.
    Taneja-Bageshwar S, Strey A, Kaczmarek K et al. Comparison of insect kinin analogs with cis-peptide bond, type VI β-turn motifs identifies optimal stereochemistry for interaction with a recombinant insect kinin receptor from the Southern cattle tick Boophilus microplus. Peptides 2008; 29(2):295–301.CrossRefPubMedGoogle Scholar
  44. 44.
    Taneja-Bageshwar S, Strey A, Zubrzak P et al. Identification of selective and nonselective, biostable β-amino acid agonists of recombinant insect kinin receptors from the Southern cattle tick Boophilus microplus and mosquito Aedes aegypti. Peptides 2008; 29(2):302–9.CrossRefPubMedGoogle Scholar
  45. 45.
    Kamoune L, De Borggraeve WM, Verbist BMP et al. Structure based design of simplified analogues of insect kinins. Tetrahedron 2005; 61:9555–62.CrossRefGoogle Scholar
  46. 46.
    Nachman RJ, Teal PEA, Strey A. Enhanced oral availability/pheromonotropic activity of peptidase-resistant topical amphiphilic analogs of pyrokinin/PBAN insect neuropeptides. Peptides 2002b; 23:2035–43.CrossRefPubMedGoogle Scholar
  47. 47.
    Cheng RP, Gellman SH, DeGrado WF. β-Peptides: From structure to function. Chem Rev 2001; 101:3219–32.CrossRefPubMedGoogle Scholar
  48. 48.
    Juaristi E, Soloshonok VA, eds. Second Edition of Enantioselective Synthesis of beta-Amino Acids. New York: Wiley, 2005.Google Scholar
  49. 49.
    Zubrzak P, Williams H, Coast GM et al. Beta-amino acid analogs of an insect neuropeptide feature potent bioactivity and resistance to peptidase hydrolysis. Biopolymers (Peptide Science) 2007; 88(1):76–2.CrossRefGoogle Scholar
  50. 50.
    Gregory H, Hardy PM, Jones PM et al. The antral hormone gastrin. Nature 1964; 204:931–3.CrossRefPubMedGoogle Scholar
  51. 51.
    Coast GM. Diuresis in the housefly (Musca domestica) and its control by neuropeptides. Peptides 2001; 22:153–60.CrossRefPubMedGoogle Scholar
  52. 52.
    Chung JS, Goldsworthy GJ, Coast GM. Haemolymph and tissue titers of achetakinins in the house cricket Acheta domesticus: effect of starvation and dehydration. J Exp Biol 1994; 193:307–19.PubMedGoogle Scholar
  53. 53.
    Goldsworthy GJ, Coast GM, Wheeler CH et al. The structural and functional activity of neuropeptides. In: Crampton JM, Eggelton P, eds. Royal Entomological Society Symposium on Insect Molecular Science. London: Academic Press, 1992:205–25.Google Scholar
  54. 54.
    Chapman KT. Synthesis of a potent, reversible inhibitor of interleukin-1b converting enzyme. Bioorg Med Chem Lett 1992; 2:613–8.CrossRefGoogle Scholar
  55. 55.
    Fehrentz JA, Heitz A, Castro B et al. Aldehydic peptides inhibiting rennin. FEBS Lett 1984; 167:273–6.CrossRefPubMedGoogle Scholar
  56. 56.
    Sarubbi E, Seneei PF, Angelestro MR et al. Peptide aldehydes as inhibitors of HIV protease. FEBS Lett 1993; 319:253–6.CrossRefPubMedGoogle Scholar
  57. 57.
    Lehninger AL. Biochemistry: the molecular basis for cell structure and function. New York: Worth Publishers, Inc, 1970:80.Google Scholar
  58. 58.
    Nachman RJ, Fehrentz JA, Martinez J et al. A C-terminal aldehyde analog of the insect kinins inhibits diuresis in the housefly. Peptides 2007; 28:146–52.CrossRefPubMedGoogle Scholar
  59. 59.
    Coast GM. Continuous recording of excretory water loss from Musca domestica using a flow-through humidity meter: hormonal control of diuresis. 2004; 50:455–68.Google Scholar
  60. 60.
    Maddrell SHP. The functional design of the insect excretory system. J Exp Biol 1981; 90:1–15.Google Scholar
  61. 61.
    O’Donnell MJ, Maddrell SHP. Paracellular and transcellular routes for water and solute movements across insect epithelia. J Exp Biol 1983; 106:231–53.PubMedGoogle Scholar
  62. 62.
    Nachman RJ, Holman GM, Haddon WF. Leads for insect neuropeptide mimetic development. Arch Insect Biochem Physiol 1994; 22:181–97.CrossRefGoogle Scholar
  63. 63.
    Reixach N, Crooks E, Ostresh JM et al. Inhibition of β-amyloid-induced neurotoxicity by imidazopyridoindoles derived from a synthetic combinatorial library. J Struct Biol 2000;130:247–58.CrossRefPubMedGoogle Scholar
  64. 64.
    Lorenz MW, Zemek R, Kodrik D et al. Lipid mobilization and locomotor atimulation in Gryllus bimaculatus by topically applied adipokinetic hormone. Physiol Entom 2004; 29:146–51.CrossRefGoogle Scholar
  65. 65.
    Nachman RJ, Teal PEA, Radel P et al. Potent pheromonotropic/myotropic activity of a carboranyl pseudotetrapeptide analog of the insect pyrokinin/PBAN neuropeptide family administered via injection or topical application. Peptides 1996; 17(5):747–52.CrossRefPubMedGoogle Scholar
  66. 66.
    Abernathy RL, Teal PEA, Meredith JA et al. Induction of moth sex pheromone production by topical application of an amphiphilic pseudopeptide mimic of pheromonotropic neuropeptides. Proc Nat Acad Sci USA 1996; 93:12621–5.CrossRefPubMedGoogle Scholar
  67. 67.
    Holman GM, Wright MS, Nachman RJ. Insect neuropeptides: Coming of age. In: Grimwade AM, ed. ISI Atlas of Science, Plants and Animals, Philadelphia: Institute for Scientific Information, Inc., 1988:212, 129–36Google Scholar
  68. 68.
    Raina AK, Jaffe H, Kempe TG et al. Identification of a neuropeptide hormone that regulates sex pheromone production in female moths. Science 1989; 244:796–8.CrossRefPubMedGoogle Scholar
  69. 69.
    Predel R, Nachman RJ. The FXPRLamide (Pyrokinin/PBAN) peptide family. In: Kastin A, ed. Handbook of Biologically Active Peptides. Elsevier, 2006:207–13.Google Scholar
  70. 70.
    Nachman RJ, Teal PEA, Ujvary I. Comparative topical pheromonotropic activity of insect pyrokinin/ PBAN amphiphilic analogs incorporating different fatty and/or cholic acid components. Peptides 2001; 22:279–85.CrossRefPubMedGoogle Scholar
  71. 71.
    Nachman RJ, Teal PEA. Amphiphilic mimics of pyrokinin/PBAN neuropeptides that induce prolonged pheromonotropic activity following topical application to a moth. In: Konopinska D, Goldsworthy G, Nachman RJ et al, eds. Insects: Chemical, Physiological and Environmental Aspects 1997. Wroclaw: University of Wroclaw Press, 1998:145–54, 293.Google Scholar
  72. 72.
    Teal PEA, Nachman RJ. Prolonged pheromonotropic activity of pseudopeptide mimics of insect pyrokinin neuropeptides after topical application or injection into a moth. Regul Pept 1997; 72:161–7.CrossRefPubMedGoogle Scholar
  73. 73.
    Teal PEA, Nachman RJ. A brominated-fluorene insect neuropeptide analog exhibits pyrokinin/PBAN-specific toxicity for adult females of the tobacco budworm moth. Peptides 2002; 23:801–6.CrossRefPubMedGoogle Scholar
  74. 74.
    Raina AK, Rafaeli A, Kingan TG. Pheromonotropic activity of orally administered PBAN and its analogs in Helicoverpa zea. J Insect Physiol 1995; 40:393–7.CrossRefGoogle Scholar
  75. 75.
    Bavoso A, Falabella P, Goacometti R et al. Intestinal absorption of proctolin in Helicoverpa armigera (Lepidoptera noctuidae) larvae. Redia 1995; 78:173–85.Google Scholar
  76. 76.
    Audsley N, Weaver RJ. In vitro transport of an allatostatin across the foregut of Manduca sexta larvae and metabolism by the gut and hemolymph. Peptides 2007; 28:136–45.CrossRefPubMedGoogle Scholar
  77. 77.
    Yao J, Feher VA, Espefo BE et al. Stabilization of a type VI turn in a family of linear peptides in water solution. J Mol Biol 1994; 243:736–53.CrossRefPubMedGoogle Scholar
  78. 78.
    Taneja-Bageshwar S, Strey A, Isaac RE et al. Biostable agonists that match or exceed activity of native insect kinins on recombinant arthropod GPCRs. Gen Comp Endocrin 2009; 162:122–128.CrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2010

Authors and Affiliations

  1. 1.Areawide Pest Management Research UnitSouthern Plains Agricultural Research Center, U.S. Department of AgricultureCollege StationUSA
  2. 2.Department of EntomologyTexas A&M UniversityCollege StationUSA

Personalised recommendations