Jürgen Scherkenbeck

Insect neuropeptides: Structures, chemical modifications and potential for insect control

Insect neuropeptides are involved in almost all physiological processes in insects, such as diuresis, ecdysis, pheromone biosynthesis and control of muscle activity. Thus, these small peptide hormones and their receptors are promising targets for a novel generation of selective and non-neurotoxic insecticides. However, due to poor bioavailability, pharmacokinetics and short half-life the peptides themselves cannot be used as insect control agents. The past two decades have seen an increase in research into the discovery of non-peptide small molecules that function as mimics for neuropeptides. This review presents an overview on structure-activity studies, conformational analyses and peptidomimetic modifications of selected insect neuropeptides with a special potential for application in pest control.

Synthesis and SERCA activities of structurally simplified cyclopiazonic acid analogues

The indole alkaloid cyclopiazonic acid (CPA) is one of the few known nanomolar inhibitors of sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA) besides the anticancer drug thapsigargin and the antiplasmoidal terpenoid artemisinin. Due to its less complex structure CPA represents an attractive lead structure for the development of novel antimalarial drugs or for applications in the field of plant protection. We report here the first syntheses of structurally simplified CPA fragments and discuss their SERCA activities on the basis of published crystal structures of CPA-SERCA complexes.

Receptor assay guided structure-activity studies of helicokinin insect neuropeptides and peptidomimetic analogues.

Neuropeptides control numerous physiological processes in insects. The regulation of water balance is a crucial aspect of homeostasis in terrestrial insects and has been shown to be under endocrine control, primarily by corticotrophin releasing factor (CRF)‐related peptides and kinins. For helicokinin I, a diuretic neuropeptide from the economically important insect pest Heliothis virescens, detailed structure‐activity relationships have been established based on truncated structures, diverse amino acid scans and peptidomimetic analogues. The activities of selected compounds on functional expressed helicokinin receptors are compared with the results of a Malphigian tubule assay. Implications for further peptidomimetic variations are provided. Copyright

Structures of Micelle-Bound Selected Insect Neuropeptides and Analogues: Implications for Receptor Selection

Neuropeptides control essential physiological processes in insects such as water balance and muscle activity. Due to their metabolic instability and adverse physiochemical properties, insect neuropeptides are unsuited for a direct application in plant protection. As a first approximation towards the biologically active conformation, the structures of selected neuropeptides from economically important pest insects were determined by NMR spectroscopy and fluorescence measurements in a membrane‐mimicking environment. A receptor binding model is suggested for the helicokinins and discussed in connection with biological activities and membrane‐bound conformations of linear and cyclic analogues.

The Natural Plant Product Rottlerin Activates Kv7.1/KCNE1 Channels.

Background/Aims: Acquired as well as inherited channelopathies are disorders that are caused by altered ion channel function. A family of channels whose malfunction is associated with different channelopathies is the Kv7 K+ channel family; and restoration of normal Kv7 channel function by small molecule modulators is a promising approach for treatment of these often fatal diseases. Methods: Here, we show the modulation of Kv7 channels by the natural compound Rottlerin heterologously expressed in Xenopus laevis oocytes and on iPSC cardiomyocytes overexpressing Kv7.1 channels. Results: We show that currents carried by Kv7.1 (EC50 = 1.48 μM), Kv7.1/KCNE1 (EC50 = 4.9 μM), and Kv7.4 (EC50 = 0.148 μM) are strongly enhanced by the compound, whereas Kv7.2, Kv7.2/Kv7.3, and Kv7.5 are not sensitive to Rottlerin. Studies on Kv7.1/KCNE1 mutants and in silico modelling indicate that Rottlerin binds to the R-L3-activator site. Rottlerin mediated activation of Kv7.1/KCNE1 channels might be a promising approach in long QT syndrome. As a proof of concept, we show that Rottlerin shortens cardiac repolarisation in iPSC-derived cardiomyocytes expressing Kv7.1.Conclusion: Rottlerin or an optimized derivative holds a potential as QT interval correcting drug.

The Bisphenol A analogue Bisphenol S binds to K-Ras4B – implications for ‘BPA-free’ plastics

K‐Ras4B is a small GTPase that belongs to the Ras superfamily of guanine nucleotide‐binding proteins. GTPases function as molecular switches in cells and are key players in intracellular signalling. Ras has been identified as an oncogene and is mutated in more than 20% of human cancers. Here, we report that Bisphenol S binds into a binding pocket of K‐Ras4B previously identified for various low molecular weight compounds. Our results advocate for more comprehensive safety studies on the toxicity of Bisphenol S, as it is frequently used for Bisphenol A‐free food containers.

Semisynthetic routes to PF1022H—A precursor for new derivatives of the anthelmintic cyclooctadepsipeptide PF1022A

The cyclooctadepsipeptide PF1022A and its semisynthetic, commercial analogue emodepside show excellent anthelmintic properties. Bis-hydroxy PF1022 (PF1022H), a minor fermentative side-product represents an interesting precursor for new PF1022 related anthelmintics. We report herein two complementary routes which allow a highly efficient conversion of PF1022A to a regioisomeric mixture consisting mainly of the bis-para isomer PF1022H and the meta-para analogue.

Macrocyclic analogues of the diuretic insect neuropeptide helicokinin I show strong receptor-binding.

Helicokinin I, a diuretic neuropeptide of the relevant cotton pest Helicoverpa zea represents a promising target for the design of insect neuropeptide mimetics. Using a ring-closing metathesis reaction, N-terminal bridged macrocyclic helicokinin I analogues with different rigidity were prepared and tested in a helicokinin receptor assay. A partially peptidomimetic helicokinin analogue, containing two structural modifications provides a deeper insight into the structural-requirements for receptor-binding.