Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 6 to 7 amino acid residues in defined sequence
Reexamination Certificate
2001-01-19
2003-12-16
Borin, Michael (Department: 1631)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
6 to 7 amino acid residues in defined sequence
C530S326000, C530S327000, C530S328000, C530S330000, C514S014800, C514S015800, C514S016700, C514S017400
Reexamination Certificate
active
06664371
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of Invention
This invention relates to mimetic pseudopeptide analogs of the allatostatin neuropeptide family, and the use of these analogs for insect control.
2. Description of the Prior Art
The allatostatin family of insect neuropeptides inhibit the in vitro biosynthesis of juvenile hormone (JH) by the corpora allata of the cockroaches
Diploptera punctata Blattella germanica
(L) and
Periplaneta americana
(Belles et al., 1994, Reg. Peptides, 53:237-247; and Weaver et al., 1994, Comp. Biochem. Physiol., 107(c):107-127). In these pests, JH plays a significant role in development reproductive maturity, sex pheromone production and mating. Specifically, a reduction in endogenous levels of JH is critical to development of the adult stage from the nymph in the cockroach, whereas oocyte growth and maturation in adult females show a dependency on the presence of JH (Bendena et al., Allatostatins: Diversity in structure and function of an insect neuropeptide family. In: Beckwith et al., Eds., Neuropeptides in Development and Aging, pp. 53-66, Annals NY Acad. Sci. 814: 53-66: 1997).
Although the allatostatins can influence a number of physiological processes by virtue of their ability to modulate in vitro production of JH, the native allatostatins have held little promise as insect control agents. The major limitations of the allatostatins which have hampered their use for insect control include their inability to penetrate the insect cuticle, and their susceptibility to inactivation by peptidases in the hemolymph and gut and/or bound to tissues within the insect (Bendena et al., ibid).
Earlier structure-activity studies have shown that the C-terminal pentapeptide Xaa
3
-Xaa
1
-Phe-Gly-Xaa
2
-NH
2
(wherein Xaa
1
occurs as any of Asn, Asp, Gly, Ser or Ala, Xaa
2
occurs as Leu or Ile, and Xaa
3
occurs as Tyr or Phe) is shared by all members of the Diploptera allatostatins, and represents the ‘active core’ region or minimum sequence capable of eliciting inhibition of JH production in vitro (Hayes et al., Peptides, 15:1165-1171, 1994; Pratt et al., Biochem. Biophys. Res. Commun., 163:1243-1247, 1989; and Pratt et al., Proc. Natl. Acad. Sci. USA, 88:2412-2416, 1991). The side chains of active core residues Phe, Leu and Tyr proved to be the most important for activity (Hayes et al., ibid). Recent studies have elucidated the primary catabolic cleavage sites of the allatostatins following incubation with hemolymph enzymes and with membrane peptidases in crude membrane preparations. Hemolymph enzymes primarily cleave the peptides in the N-terminal region outside of the pentapeptide core region and therefore, do not inactivate the allatostatins (Garside et al., Peptides, 18:17-25, 1997). However, membrane preparations of brain, gut and corpora allata cleave allatostatins at the C-terminus between residues Gly-Leu, with secondary cleavage occuring between the residue block Xaa
3
-Xaa
1
(Garside et al., Gen. Comp. Endocrinol., 108:258-270, 1997). Both of these cleavages disrupt the active core sequence and lead to completely inactive fragments.
The contents of each of the above-mentioned publications are incorporated by reference herein.
SUMMARY OF THE INVENTION
We have discovered novel pseudopeptide analogs of the insect allatostatin neuropeptide family which possess biological activity mimicking that of the naturally occurring neuropeptides. By addition of a hydrophobic moiety to an active portion of the allatostatin peptides, analogs are produced, which exhibit an overall amphiphilic nature and which are capable of penetrating the insect cuticle while still retaining biological activity. Furthermore, by substituting sterically hindered amino acids or aromatic acids for any or all of the second, third or fifth amino acid residues of the allatostatin C-terminal pentapeptide, analogs have been produced which are resistant to degradation by insect peptidases while still retaining biological activity. The analogs may be used for insect control by disrupting critical reproductive and/or developmental processes normally regulated by allatostatins in insects.
In accordance with this discovery, it is an object of this invention to provide novel compounds having biological activity mimicking that of the naturally occurring allatostatin neuropeptides.
It is also an object of this invention to provide compounds which are bioactive mimics of allatostatin neuropeptides that are capable of penetrating the insect cuticle.
Another object is to provide compounds which are bioactive mimics of allatostatin neuropeptides which are resistant to enzyme degradation.
Yet another object is to provide compounds which are bioactive mimics of allatostatin neuropeptides and their use for controlling insect populations and which may be topically applied.
Other objects and advantages of the invention will become readily apparent from the ensuing description.
REFERENCES:
patent: 5039792 (1991-08-01), Feyerisen et al.
patent: 5358934 (1994-10-01), Borovsky et al.
patent: 5679797 (1997-10-01), Kempf et al.
patent: 97/35981 (1997-10-01), None
Xaus et al. Int. J. Peptide Protein Res., 39, pp. 528-532,1992.
Garside Christopher S.
Nachman Ronald J.
Teal Peter E. A.
Tobe Stephen S.
Borin Michael
Deck Randall E.
Fado John D.
The United States of America as represented by the Secretary of
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