Interaction of mimetic analogs of insect kinin neuropeptides with arthropod receptors.

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 ofthe 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 ofa 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 ofdiuresis in the housefly. Strategies for the modification of insect neuropeptide structures for the enhancement ofthe 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.