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trans-Pro isosteres in the development of non-selective and selective mimetic agonists of insect pyrokinin neuropeptides: A review

100%

Nachman R. J.

Pestycydy

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2009

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nr 1-4

33-39

The pyrokinin (PK) family plays a multifunctional role in an array of important physiological processes in a variety of insects. A PK active core analog containing an (E)-alkene, transPro isosteric component was evaluated in five disparate PK bioassays and/or in a recombinant PK receptor cell line, representing six different insect species. The assays included pheromone biosynthesis in the moth Heliothis peltigera, melanization in the larval Spodoptera littoralis, pupariation acceleration in the larval fly Neobellieria bullata, diapause termination in the moth Heliothis zea, and hindgut contraction in the cockroach Leucophaea maderae. This constrained analog demonstrated unselective agonist activity that approached, matched, or exceeded the activity of parent PK peptides of equal length in all six PK assays. The results provide strong evidence for the orientation of Pro and the core conformation adopted by PK neuropeptides during interaction with disparate PK receptors. A PK active core analog incorporating a second transPro motif, the dihydroimidazoline moiety, was found to demonstrate pure, selective agonism in the melanotropic bioassay, with no significant activity in three other PK bioassays. Both types of transPro isosteric analogs feature modification adjacent to the primary tissue-bound peptidase hydrolysis site that is expected to enhance biostability over natural PK peptides. The research further identifies two novel scaffolds with which to design either selective or non-selective mimetic PK analogs as potential leads in the development of environmentally favorable pest management agents capable of disrupting PK-regulated systems.

2

Biostable analogs of insect kinin and insectatachykinin neuropeptides: A review of novel classes of antifeedants and aphicides

63%

Nachman R. J., Smagghe G.

Pestycydy

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2011

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nr 1-4

Neuropeptides are regulators of critical life processes in insects, but are subject to rapid degradation by peptidases in the hemolymph (blood), tissues and gut. This limitation can be overcome via replacement of peptidase susceptible portions of the insect neuropeptides with non-natural residues or moieties to create analogs with enhanced biostability. Two neuropeptide families, the insect kinins and insectatachykinins, stimulate gut motility and Malpighian tubule fluid secretion in certain insects but unmodified members demonstrate little or no effect when fed to pea aphids (Acyrthosiphon pisum) in an artificial diet. Nonetheless, biostable analogs developed via the strategic introduction of either bulky Aib residues and/or β-amino acids demonstrate potent antifeedant and aphicidal effects when administered orally; whereas other biostable analogs are inactive. Although the precise mechanism of action has not been delineated, the activity may be associated with disruption of the physiological processes that these neuropeptides regulate in insects. The most active of the biostable insect kinin and insectatachykinin analogs show LC50 values of 0.063 nmole/μl (LT50 = 1.68 days) and 0.0085 nmole/μl (LT50 = 1.1 days), respectively; matching or exceeding the potency of some commercially available aphicides. The biostable analogs represent important leads in the development of alternative, environmentally sound aphid control agents.

3

MALDI-TOF-TOF mass spectrometric assignment of Leu-Ile in PVK-CAP2b neuropeptides from single neurohemal organ preparations of four flies

51%

Nachman R. J., Russell W. K., Russell D. H., Predel R.

Pestycydy

|

2005

|

nr 3

49-53

4

Structure-activity relationships for insect kinins on expressed receptors from a tick [Acari: Ixodidae] and a mosquito [Diptera: Culicidae]

45%

Taneja-Bageshwar S., Strey A., Zubrzak P., Pietrantonio P. V., Nachman R. J.

Pestycydy

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2005

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nr 3

55-59

5

A beta-amino acid pyrokinin analog induces irregular pupariation behavior in larvae of the flesh fly Sarcophaga bullata

45%

Nachman R. J., Zubrzak P., Williams H., Strey A., Zdarek J.

Pestycydy

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2008

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nr 1-2

95-100

The developmental process of pupariation is accelerated by members of the pyrokinin class of neuropeptides in larvae of the flesh fly Sarcophaga bullata. A pyrokinin analog (Ac-Y[β3Phe]TPRLamide), in which a Phe residue is replaced with a β-amino acid, accelerates pupariation in this fly at a potency (0.2 pmol/larva) that matches that of the native pyrokinin factor. At higher concentrations, this β-amino acid pyrokinin analog induces irregular pupariation behavior patterns that are suggestive of neurotoxic properties. Biostable analogs based on this structure may in future provide analog leads with the potential to disrupt the important pupariation process in flies.

6

Stereochemistry of insect kinin tetrazole analogues and their diuretic activity in crickets

45%

Nachman R. J., Coast G. M., Kaczmarek K., Wiliams H. J., Zabrocki J.

Acta Biochimica Polonica

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2004

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tom 51

|

nr 1

Insect kinin analogues of the sequence Phe-Phe-Ψ[CN4]-Ala-Trp-Gly-NH2 containing (L-Phe2,L-Ala3) and (L-Phe2,D-Ala3) stereochemical variants of the tetrazole moiety, a mimic of the type VI -turn, demonstrate significant agonist and partial antagonist activity, respectively, in a cricket diuretic bioassay. A comparison of the solution conformations of these two stereochemical variants indicates a structural basis for their divergent bioactivities. The (D-Phe2,D-Ala3) stereochemical variant was synthesized and found to demonstrate significant agonist activity. The results further define stereochemical requirements for the diuretic activity of insect kinins in crickets and provide valuable information for the design of biostable analogues capable of disrupting digestive and diuretic processes in pest insects.

7

Identification of a CAPA-PVK [Ixori-PVK] from single cells of the gulf Gulf Coast tick, Amblyomma maculatum

39%

Neupert S., Russell W. K., Russell D. H., Strey O. F., Teel P. D., Strey A., Nachman R. J.

Pestycydy

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2008

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nr 1-2

67-73

MALDI-TOF/TOF tandem mass spectrometry has been applied to determine the complete sequence of a CAPA-PVK in the Gulf Coast tick, Amblyomma maculatum. Single cell analysis allowed the identification of the amino acid sequence of Ixori-PVK (PALIPFPRV-NH2), a periviscerokinin which had previously been identified from two other ticks, Ixodes ricinus and Boophilus microplus. The identification indicates greater conservation of sequence for the CAPA-PVK/CAP2b family in ticks as compared with insects. Side-chain fragmentation experiments provided data to distinguish between Leu/Ile ambiguities. The tick CAPA peptide shows a high sequence homology with other members of the insect periviscerokinin/ CAP2b peptides, which are associated with the regulation of critical physiological processes such as diuresis. Thus, the identification of this neuropeptide will provide the experimental basis to better understand regulation of water balance in these arthropods, providing a potential opportunity to develop neuropeptide-based control strategies against these livestock pests.

8

Chelating ability of proctolin tetrazole analogue

39%

Lodyga-Chruscinska E., Sanna D., Micera G., Chruscinski L., Olejnik J., Nachman R. J., Zabrocki J.

Acta Biochimica Polonica

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2006

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tom 53

|

nr 1

The aim of the investigation was to establish the chelating ability of a new proctolin analogue of the sequence Arg-Tyr-LeuΨ[CN4]Ala-Thr towards copper(II) ions. The insertion of the tetrazole moiety into the peptide sequence has considerably changed the coordination ability of the ligand. Potentiometric and spectroscopic (UV-Vis, CD, EPR) results indicate that the incorporation of 1,5-disubstituted tetrazole ring favours the formation of a stable complex form of CuH-1L. This 4N coordination type complex is the dominant species in the physiological pH range. The tetrazole moiety provides one of these nitrogens. The data indicate that Cu(II) ions are strongly trapped inside the peptide backbone. These findings suggest that Cu(II) can hold peptide chains in a bent conformation. This bent conformation may be essential for bioactivity of the tetrazole peptides.

Ograniczanie wyników

trans-Pro isosteres in the development of non-selective and selective mimetic agonists of insect pyrokinin neuropeptides: A review

Biostable analogs of insect kinin and insectatachykinin neuropeptides: A review of novel classes of antifeedants and aphicides

MALDI-TOF-TOF mass spectrometric assignment of Leu-Ile in PVK-CAP2b neuropeptides from single neurohemal organ preparations of four flies

Structure-activity relationships for insect kinins on expressed receptors from a tick [Acari: Ixodidae] and a mosquito [Diptera: Culicidae]

A beta-amino acid pyrokinin analog induces irregular pupariation behavior in larvae of the flesh fly Sarcophaga bullata

Stereochemistry of insect kinin tetrazole analogues and their diuretic activity in crickets

Identification of a CAPA-PVK [Ixori-PVK] from single cells of the gulf Gulf Coast tick, Amblyomma maculatum

Chelating ability of proctolin tetrazole analogue