Neuropeptide signalling systems – An underexplored target for venom drug discovery

Mendel, Helen C.; Kaas, Quentin; Muttenthaler, Markus

doi:10.1016/j.bcp.2020.114129

Cited by 22 publications

(11 citation statements)

References 173 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[73][74][75] Venom peptides target 2 predominant families of membrane-bound proteins, ion channels and GPCR, including neuropeptide GPCR. 15,76,77 For instance, peptides Pn3a from the tarantula Pamphobeteus nigricolor, MT7 from the green mamba Dendroaspis angusticeps, and [Thr 6 ]BK from the neotropical wasp Polybia occidentalis are ligands of voltage-gated sodium channel Na V 1.7, type-1 muscarinic, and type-2 bradykinin receptors, respectively. [78][79][80] Recently, we have deciphered the molecular diversity of the T bicarinatum ant venom, which encompasses 37 peptide precursors processed into several thousand peptides in the venom, 81 a source of structural templates for new therapeutics or bioactive agents.…”

Section: Discussionmentioning

confidence: 99%

P17 induces chemotaxis and differentiation of monocytes via MRGPRX2-mediated mast cell–line activation

Duraisamy

Singh

Kumar

et al. 2022

Journal of Allergy and Clinical Immunology

View full text Add to dashboard Cite

Background: P17, a peptide isolated from Tetramorium bicarinatum ant venom, is known to induce an alternative phenotype of human monocyte-derived macrophages via activation of an unknown G protein-coupled receptor (GPCR). Objective: We sought to investigate the mechanism of action and the immunomodulatory effects of P17 mediated through MRGPRX2 (Mas-related G protein-coupled receptor X2). Methods: To identify the GPCR for P17, we screened 314 GPCRs. Upon identification of MRGPRX2, a battery of in silico, in vitro, ex vivo, and in vivo assays along with the receptor mutation studies were performed. In particular, to investigate the immunomodulatory actions, we used b-hexosaminidase release assay, cytokine releases, quantification of mRNA expression, cell migration and differentiation assays, immunohistochemical labeling, hematoxylin and eosin, and immunofluorescence staining. Results: P17 activated MRGPRX2 in a dose-dependent manner in b-arrestin recruitment assay. In LAD2 cells, P17 induced calcium and b-hexosaminidase release. Quercetin-and short hairpin RNA-mediated knockdown of MRGPRX2 reduced P17evoked b-hexosaminidase release. In silico and in vitro mutagenesis studies showed that residue Lys 8 of P17 formed a cation-p interaction with the Phe 172 of MRGPRX2 and [Ala 8 ] P17 lost its activity partially. P17 activated LAD2 cells to recruit THP-1 and human monocytes in Transwell migration assay, whereas MRGPRX2-impaired LAD2 cells cannot. In addition, P17-treated LAD2 cells stimulated differentiation of THP-1 and

show abstract

Section: Discussionmentioning

confidence: 99%

P17 induces chemotaxis and differentiation of monocytes via MRGPRX2-mediated mast cell–line activation

Duraisamy

Singh

Kumar

et al. 2022

Journal of Allergy and Clinical Immunology

View full text Add to dashboard Cite

show abstract

“…Disulfide bond-containing neuropeptides are essential signaling molecules, and their receptors recognized drug targets under various conditions, including gastrointestinal disorders. ,,− We therefore probed the gastrointestinal stability of important examples along with their approved drug variants (Figure C). The presence of multiple sequential aromatic amino acids renders the endocrine hormone somatostatin a model substrate for pepsin activity and resulted in a short half-life of t 1/2 SGF = 13 ± 2 min in SGF (Figures D and S1).…”

Section: Resultsmentioning

confidence: 99%

On the Utility of Chemical Strategies to Improve Peptide Gut Stability

et al. 2022

Self Cite

View full text Add to dashboard Cite

Inherent susceptibility of peptides to enzymatic degradation in the gastrointestinal tract is a key bottleneck in oral peptide drug development. Here, we present a systematic analysis of (i) the gut stability of disulfide-rich peptide scaffolds, orally administered peptide therapeutics, and well-known neuropeptides and (ii) medicinal chemistry strategies to improve peptide gut stability. Among a broad range of studied peptides, cyclotides were the only scaffold class to resist gastrointestinal degradation, even when grafted with non-native sequences. Backbone cyclization, a frequently applied strategy, failed to improve stability in intestinal fluid, but several site-specific alterations proved efficient. This work furthermore highlights the importance of standardized gut stability test conditions and suggests defined protocols to facilitate cross-study comparison. Together, our results provide a comparative overview and framework for the chemical engineering of gut-stable peptides, which should be valuable for the development of orally administered peptide therapeutics and molecular probes targeting receptors within the gastrointestinal tract.

show abstract

“…Neuropeptides are initially synthesized within the cell soma and stored in large dense core vesicles in axon terminals until their release. Centrally synthesized sensory neuropeptides often act as neuromodulators, enhancing or dampening the activity of co-stored neuropeptides ( Merighi, 2002 ) or co-released neurotransmitters ( Gibbins et al, 1985 , Russo, 2017 ) to modulate synaptic signaling, in addition to acting as signaling molecules themselves (reviewed in Mendel et al [2020] ). In contrast, peripherally synthesized neuropeptides behave as signaling molecules ( Schlereth et al, 2016 ) and bind to surface receptors on target tissues, other peripheral nerves, and cells in the ganglia.…”

Section: Sensory Neuropeptidesmentioning

confidence: 99%