ARS | Publication request: Analogs of sulfakinin-related peptides demonstrate reduction in food intake in the red flour beetle, Tribolium castaneum, while putative antagonists increase consumption

Submitted to: Peptides
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: December 6, 2012
Publication Date: N/A

Interpretive Summary: Insect pests have developed resistance to several conventional pesticides, and new approaches are needed for pest management. Although neuropeptides (short chains of amino acids) serve as potent messengers in insects to regulate vital functions, the neuropeptides hold little promise as pest control agents because they can be degraded in the target pest. New, selective control agents may be developed by designing mimics of these neuropeptides that resist degradation and either inhibit or over-stimulate critical neuropeptide-regulated life functions. This paper describes work that demonstrates that neuropeptides of the ‘sulfakinin’ class can reduce food intake by 70% in the red flour beetle, an important insect pest of stored grain. The paper also provides evidence that this activity takes place via a specific interaction with a neuropeptide active site and therefore represents an entirely novel mode of action. Structural studies have shed light on how sulfakinin peptides interact with this active site. The discoveries revealed in this paper will aid in the design of neuropeptide-like compounds capable of disrupting both the feeding and digestive functions of pest insects. The work brings us one step closer to the development of practical neuropeptide-like substances that will be effective in controlling pest insects in an environmentally friendly fashion.

Technical Abstract: The insect sulfakinins (SKs) constitute a family of neuropeptides that display both structural and functional similarities to the mammalian hormones gastrin and cholecystokinin (CCK). As a multifunctional neuropeptide, SKs are involved in muscle contractions as well as food intake regulation in many insects. In the red flour beetle Tribolium castaneum, the action on food intake by a series of synthetic SK analogs and one putative antagonist was investigated by injection in beetle adults. The most remarkable result was that both sulfated and non-sulfated SKs [FDDY(SO3H)GHMRFamide] inhibited food intake by about 70%. Strong activity observed for SK analogs featuring a residue that mimics the acidic nature of Tyr(SO3H) but lack the phenyl ring of Tyr, indicate that aromaticity is not a critical characteristic for this position of the peptide. SK demonstrated considerable tolerance to Ser and Ala substitution in position 8 (basic Arg), as analogs featuring these uncharged substitutions retained almost all of the food intake inhibitory activity. Also, the Phe in position 1 could be replaced by Ser without complete loss of activity. Conversely, substitution of Met by Nle in position 3 led to inactive compounds. Finally, the Caenorhabditis elegans sulfated neuropeptide-like protein-12 (NLP-12), that shares some sequence similarities with the SKs but features a Gln-Phe-amide rather than an Arg-Phe-amide at the C-terminus, elicited increased food intake in T. castaneum, which may indicate an antagonist activity. Co-injection NLP-12 with nsSK blocked the food intake inhibitory effects of nsSK.