Structure-function relationship of new peptides activating human Na1.1.

Na1.1 is an important pharmacological target as this voltage-gated sodium channel is involved in neurological and cardiac syndromes. Channel activators are actively sought to try to compensate for haploinsufficiency in several of these pathologies.

From a Cone Snail Toxin to a Competitive MC4R Antagonist.

The melanocortin 4 receptor (MC4R) plays a role in energy homeostasis and represents a target for treating energy balance disorders. For decades, synthetic ligands have been derived from MC4R endogenous agonists and antagonists, such as setmelanotide used to treat rare forms of genetic obesity. Recently, animal venoms have demonstrated their capacity to provide melanocortin ligands with toxins from a scorpion and a spider.

MT9, a natural peptide from black mamba venom antagonizes the muscarinic type 2 receptor and reverses the M2R-agonist-induced relaxation in rat and human arteries.

All five muscarinic receptors have important physiological roles. The endothelial M2 and M3 subtypes regulate arterial tone through direct coupling to Gq or Gi/o proteins. Yet, we lack selective pharmacological drugs to assess the respective contribution of muscarinic receptors to a given function.

2-Hydroxy-4-methoxybenzyl as a Thiol-Protecting Group for Directed-Disulfide Bond Formation.

The chemical synthesis of disulfide-rich peptides such as toxins can be accomplished by using numerous orthogonal cysteine-protecting groups. Herein we report the use of the Hmb protecting group for directed disulfide bond formation. Its combination with classical Trt, Acm, and Mob groups was studied for the synthesis of NMB-1 and phlotoxin-1 toxins highlighting new orthogonal strategies for directed disulfide bond formation.

Chemical Synthesis of a Functional Fluorescent-Tagged α-Bungarotoxin.

α-bungarotoxin is a large, 74 amino acid toxin containing five disulphide bridges, initially identified in the venom of snake. Like most large toxins, chemical synthesis of α-bungarotoxin is challenging, explaining why all previous reports use purified or recombinant α-bungarotoxin. However, only chemical synthesis allows easy insertion of non-natural amino acids or new chemical functionalities.

In vivo spatiotemporal control of voltage-gated ion channels by using photoactivatable peptidic toxins.

Photoactivatable drugs targeting ligand-gated ion channels open up new opportunities for light-guided therapeutic interventions. Photoactivable toxins targeting ion channels have the potential to control excitable cell activities with low invasiveness and high spatiotemporal precision. As proof-of-concept, we develop HwTxIV-Nvoc, a UV light-cleavable and photoactivatable peptide that targets voltage-gated sodium (Na) channels and validate its activity in vitro in HEK293 cells, ex vivo in brain slices and in vivo on mice neuromuscular junctions.

Synthetic Analogues of Huwentoxin-IV Spider Peptide With Altered Human Na1.7/Na1.6 Selectivity Ratios.

Huwentoxin-IV (HwTx-IV), a peptide discovered in the venom of the Chinese bird spider , has been reported to be a potent antinociceptive compound due to its action on the genetically-validated Na1.7 pain target. Using this peptide for antinociceptive applications suffers from one major drawback, namely its negative impact on the neuromuscular system.

Fluorescent- and tagged-protoxin II peptides: potent markers of the Na 1.7 channel pain target.

Background And Purpose: Protoxin II (ProTx II) is a high affinity gating modifier that is thought to selectively block the Na 1.7 voltage-dependent Na channel, a major therapeutic target for the control of pain. We aimed at producing ProTx II analogues entitled with novel functionalities for cell distribution studies and biochemical characterization of its Na channel targets.

Heterodimeric Insecticidal Peptide Provides New Insights into the Molecular and Functional Diversity of Ant Venoms.

Ants use venom for predation, defense, and communication; however, the molecular diversity, function, and potential applications of ant venom remains understudied compared to other venomous lineages such as arachnids, snakes and cone snails. In this work, we used a multidisciplinary approach that encompassed field work, proteomics, sequencing, chemical synthesis, structural analysis, molecular modeling, stability studies, and and bioassays to investigate the molecular diversity of the venom of the Amazonian ants. We isolated a potent insecticidal heterodimeric peptide Δ-pseudomyrmecitoxin-Pp1a (Δ-PSDTX-Pp1a) composed of a 27-residue long A-chain and a 33-residue long B-chain cross-linked by two disulfide bonds in an antiparallel orientation.

Chemical Synthesis, Proper Folding, Na Channel Selectivity Profile and Analgesic Properties of the Spider Peptide Phlotoxin 1.

Phlotoxin-1 (PhlTx1) is a peptide previously identified in tarantula venom ( species) that belongs to the inhibitory cysteine-knot (ICK) toxin family. Like many ICK-based spider toxins, the synthesis of PhlTx1 appears particularly challenging, mostly for obtaining appropriate folding and concomitant suitable disulfide bridge formation. Herein, we describe a procedure for the chemical synthesis and the directed sequential disulfide bridge formation of PhlTx1 that allows for a straightforward production of this challenging peptide.

Fluorescent analogues of BeKm-1 with high and specific activity against the hERG channel.

Peptidic toxins that target specifically mammalian channels and receptors can be found in the venom of animals. These toxins are rarely used directly as tools for biochemical experiments, and need to be modified via the attachment of chemical groups (e.g.

From identification to functional characterization of cyriotoxin-1a, an antinociceptive toxin from the spider Cyriopagopus schioedtei.

Background And Purpose: The Na 1.7 channel is highly expressed in dorsal root ganglia of the sensory nervous system and plays a central role in the pain signalling process. We investigated a library prepared from original venoms of 117 different animals to identify new selective inhibitors of this target.

Synthesis by native chemical ligation and characterization of the scorpion toxin AmmTx3.

The scorpion toxin AmmTx3 is a specific blocker of K4 channels. It was shown to have interesting potential for neurological disorders. In this study, we report the first chemical synthesis of AmmTx3 by using the native chemical ligation strategy and validate its biological activity.

Actiflagelin, a new sperm activator isolated from venom using phenotypic screening.

Background: Sperm contains a wealth of cell surface receptors and ion channels that are required for most of its basic functions such as motility and acrosome reaction. Conversely, animal venoms are enriched in bioactive compounds that primarily target those ion channels and cell surface receptors. We hypothesized, therefore, that animal venoms should be rich enough in sperm-modulating compounds for a drug discovery program.

Functional characterization of cell-free expressed K1.3 channel using a voltage-sensitive fluorescent dye.

Using a cell-free expression system, we produced the K1.3 protein embedded in one step within detergent micelles. The protein was then purified and relipidated into mixed lipid bilayers.