Cyclic Peptides that Govern Signal Transduction Pathways: From Prokaryotes to Multi-Cellular Organisms

Abstract

Cyclic peptide scaffolds are key components of signal transduction pathways in both prokaryotic and eukaryotic organisms since they act as chemical messengers that activate or inhibit specific cognate receptors. In prokaryotic organisms these peptides are utilized in non-essential pathways, such as quorum sensing, that are responsible for virulence and pathogenicity. In the more evolved eukaryotic systems, cyclic peptide hormones play a key role in the regulation of the overall function of multicellular organisms, mainly through the endocrine system. This review will highlight several prokaryote and eukaryote systems that use cyclic peptides as their primary signals and the potential associated with utilizing these scaffolds for the discovery of novel therapeutics for a wide range of diseases and illnesses.

Keywords: Cyclic peptides; autoinducers; eukaryotes; hormones; prokaryotes; quorum sensing; signal transduction..

Figure 1

Generalized QS circuit utilized by Gram-positive species. A) The signal precursor is processed by the endopeptidase to afford the mature AIP; B) The endopeptidase then exports the AIP to the extracellular environment; C) Once the extracellular concentration of the AIP reaches a minimal sensory level, it is detected by the histidine kinase receptor; D) When the AIP binds to the histidine kinase receptor it autophosphorylates, causing a phosphate group to be transferred to the response regulator; E) The response regulator activates the transcription of early gene products; F) The response regulator triggers transcription of the effector molecule, which is responsible for the activation of a multitude of group behavior genes.

Figure 2

The AIP signals utilized by different staphylococcal species.

Figure 3

Select synthetic S. aureus AIP-based antagonists synthesized by Williams and co-workers,[40] Novick, Muir and co-workers,[24] and Blackwell and co-workers.[45, 56] Shaded amino acids and groups indicate modification from the native peptide sequence. Ac, Acetyl; Dap, Diaminopropionic acid.

Figure 4

Select synthetic S. epidermidis AIPs. The lactone and lactam derivatives were designed by Otto and co-workers, and displayed reduced agonistic activity compared to the native AIP-I peptide.[63] AIP-I D1AS6AV3A and AIP-1 D1AS6AV3AA5S were determined to be pan group AgrC inhibitors, while AIP-I D1AS6A was found to be a non-native agonist with improved potency over the native peptide.[64] Shaded amino acids indicate modification from the native peptide sequence. Dap, Diaminopropionic acid. * EC₅₀ value not available.

Figure 5

The gelatinase biosynthesis activating pheromone (GBAP) utilized by the fsr QS circuit in E. faecalis and several synthetic peptide analogs. Lactam-GBAP, thiolactone-GBAP, and CH₂-lactone-GBAP all displayed agonistic activity, while disulfide-GBAP did not show any agonistic or antagonistic activity.[77] ZBzl-YAA5911 is the most potent fsr QS antagonist identified thus far.[78] Shaded amino acids and groups indicate modification from the native peptide sequence. Z, benzyloxycarbonyl; Bzl, benzyl; Dap, Diaminopropionic acid; Hse, homoserine. * EC₅₀ value not available

Figure 6

Select synthetic Clostridium AIPs found to have either agonistic or antagonistic activity against the C. perfringens or C. acetobutylicum QS circuits. Peptides 8-R and 5-R were found to have agonistic activity on the C. perfringens QS circuit, while Peptide 6-R was found to be a C. perfringens QS antagonist.[89] Peptide R6T0 was determined to have high agonistic activity on the C. acetobutylicum QS circuit.[88]

Figure 7

Structure of the AIP utilized by L. plantarum.

Figure 8

Diagram of hormone maturation process. A: Preprohormone mRNA is translated into preprohormone by the ribosome. B: Preprohormone has signal peptide cleaved as it passes through translocon into the rough ER. C: Prohormone folds into its correct structure in rough ER. D: Cleavage of prohormone into mature hormone prior to be transported to the Golgi complex for packaging and secretion.

Figure 9

Various cyclic peptide hormones associated with eukaryotes.

Figure 10

Bioactive somatostatin isoforms along with a few of their synthetic analogs. Non-natural amino acids are shaded. Lower case letters indicate D-amino acids; D^2* is 3-(2-Naphthyl)-D-alanine; T^ol is L-Threoninol.

Figure 11

Native insulin and various FDA approved analogs. Shaded amino acids and groups indicate modification from the native peptide sequence.

Figure 12

Oxytocin and various synthetic analogs. Shaded amino acids and groups indicate modification from the native peptide sequence.

Figure 13

Vasopressin and various synthetic analogs. Shaded amino acids and groups indicate modification from the native peptide sequence. Lower case letters indicate D-amino acids. Hgn, homoglutamine.