Solid phase synthesis of an insect pyrokinin analog incorporating an imidazoline ring as isosteric replacement of a trans peptide bond

Authors: KACZMAREK, KRZYSZTOF - Technical University Of Lodz; PACHOLCZYK-SIENICKA, BARBARA - Technical University Of Lodz; ALBRECHT, LUKASZ - Technical University Of Lodz; ZABROCKI, JANUSZ - Technical University Of Lodz; NACHMAN, RONALD - Retired ARS Employee

Submitted to: Molecules
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/17/2021
Publication Date: 5/28/2021
Citation: Kaczmarek, K., Pacholczyk-Sienicka, B., Albrecht, L., Zabrocki, J., Nachman, R.J. 2021. Solid phase synthesis of an insect pyrokinin analog incorporating an imidazoline ring as isosteric replacement of a trans peptide bond. Molecules. 26:3271-3279. https://doi.org/10.3390/molecules26113271.
DOI: https://doi.org/10.3390/molecules26113271

Interpretive Summary: Because of the development of resistance to conventional pesticides, there is a critical need for new concepts and alternative approaches in controlling insect pests. The basic premise of this research is that neuropeptides (short chains of amino acids) serve as potent hormone messengers in insects to regulate vital functions. Nevertheless, neuropeptides in and of themselves hold little promise as pest control agents because of their inability to penetrate the outer shell of insects and rapid degradation within the target pest. New, selective control measures may be developed by designing stable mimics of these neuropeptide hormones that interact with the active site within the agricultural pest in such a way as to either inhibit or over-stimulate critical neuropeptide-regulated life functions. In this study, we describe the development of a new and practical ‘solid-phase’ method to incorporate a component into neuropeptides that stabilizes and still mimics the neuropeptide structure required by these hormones to regulate critical life processes. Because they are stabilized and not easily degraded, the resulting modified neuropeptides disrupt those critical life processes and can induce high mortality in treated pest insects. This new method is also applicable to biologically active peptides with medical applications. The methodology will facilitate the design and development of practical neuropeptide-like substances that can function as environmentally friendly and effective agents for the control of pest insect populations that are safe to beneficial insects like the honeybee.

Technical Abstract: A facile solid-phase synthetic method for incorporating the imidazoline ring motif, a surrogate for a trans peptide bond, into bioactive peptides is reported. The example described is the synthesis of an imidazoline peptidomimetic analog of an insect pyrokinin neuropeptide via a cyclization re-action of an iminium salt generated from the preceding amino acid and 2,4-diaminopropanoic acid (Dap).