Fatty acid chain modification enhances the serum stability of antimicrobial peptide B1 and activities against Staphylococcus aureus and Klebsiella pneumoniae.

Antimicrobial peptides (AMPs) possess broad-spectrum antibacterial properties and low resistance development, making them promising candidates for new antibacterial drugs. Incorporating fatty acid chains into AMPs can increase their hydrophobicity, strengthen membrane affinity, and improve their antibacterial effectiveness and stability. This study introduces fatty acid chains of varying lengths into the naturally derived antimicrobial peptide B1.

The α3β4 nAChR tissue distribution identified by fluorescent α-conotoxin [D11A]LvIA.

α3β4, a vital subtype of neuronal nicotinic acetylcholine receptors (nAChRs), is widely distributed in the brain, ganglia, and adrenal glands, associated with addiction and neurological diseases. However, the lack of specific imaging tools for α3β4 nAChRs has hindered the investigation of their tissue distribution and functions. [D11A]LvIA, a peptide derived from marine cone snails, demonstrates high affinity and potency for α3β4 nAChRs, making it a valuable pharmacological tool for studying this receptor subtype.

Single Amino Acid Substitution in Loop1 Switches the Selectivity of α-Conotoxin RegIIA towards the α7 Nicotinic Acetylcholine Receptor.

α-Conotoxins are disulfide-rich peptides obtained from the venom of cone snails, which are considered potential molecular probes and drug leads for nAChR-related disorders. However, low specificity towards different nAChR subtypes restricts the further application of many α-conotoxins. In this work, a series of loop1 amino acid-substituted mutants of α-conotoxin RegIIA were synthesized, whose potency and selectivity were evaluated by an electrophysiological approach.

Stapling Cysteine[2,4] Disulfide Bond of α-Conotoxin LsIA and Its Potential in Target Delivery.

α-Conotoxins, as selective nAChR antagonists, can be valuable tools for targeted drug delivery and fluorescent labeling, while conotoxin-drug or conotoxin-fluorescent conjugates through the disulfide bond are rarely reported. Herein, we demonstrate the [2,4] disulfide bond of α-conotoxin as a feasible new chemical modification site. In this study, analogs of the α-conotoxin LsIA cysteine[2,4] were synthesized by stapling with five linkers, and their inhibitory activities against human α7 and rat α3β2 nAChRs were maintained.

Conotoxins Targeting Voltage-Gated Sodium Ion Channels.

Voltage-gated sodium (Na) channels are intimately involved in the generation and transmission of action potentials, and dysfunction of these channels may contribute to nervous system diseases, such as epilepsy, neuropathic pain, psychosis, autism, and cardiac arrhythmia. Many venom peptides selectively act on Na channels. These include conotoxins, which are neurotoxins secreted by cone snails for prey capture or self-defense but which are also valuable pharmacological tools for the identification and/or treatment of human diseases.

Fluorescent α-Conotoxin [Q1G, ΔR14]LvIB Identifies the Distribution of Nicotinic Acetylcholine Receptor in the Rat Brain.

nicotinic acetylcholine receptors (nAChRs) are mainly distributed in the central nervous system (CNS), including the hippocampus, striatum, and cortex of the brain. The nAChR has high Ca permeability and can be quickly activated and desensitized, and is closely related to Alzheimer's disease (AD), epilepsy, schizophrenia, lung cancer, Parkinson's disease (PD), inflammation, and other diseases. α-conotoxins from marine cone snail venom are typically short, disulfide-rich neuropeptides targeting nAChRs and can distinguish various subtypes, providing vital pharmacological tools for the functional research of nAChRs.

Aspartic acid mutagenesis of αO-Conotoxin GeXIVA isomers reveals arginine residues crucial for inhibition of the α9α10 nicotinic acetylcholine receptor.

The two most active disulfide bond isomers of the analgesic αO-conotoxin GeXIVA, namely GeXIVA[1, 2] and GeXIVA[1, 4], were subjected to Asp-scanning mutagenesis to determine the key amino acid residues for activity at the rat α9α10 nicotinic acetylcholine receptor (nAChR). These studies revealed the key role of arginine residues for the activity of GeXIVA isomers towards the α9α10 nAChR. Based on these results, additional analogues with 2-4 mutations were designed and tested.

Engineering Enhanced Antimicrobial Properties in α-Conotoxin RgIA through D-Type Amino Acid Substitution and Incorporation of Lysine and Leucine Residues.

Antimicrobial peptides (AMPs), acknowledged as host defense peptides, constitute a category of predominant cationic peptides prevalent in diverse life forms. This study explored the antibacterial activity of α-conotoxin RgIA, and to enhance its stability and efficacy, D-amino acid substitution was employed, resulting in the synthesis of nine RgIA mutant analogs. Results revealed that several modified RgIA mutants displayed inhibitory efficacy against various pathogenic bacteria and fungi, including and .

αO-Conotoxin GeXIVA[1,2] Reduced Neuropathic Pain and Changed Gene Expression in Chronic Oxaliplatin-Induced Neuropathy Mice Model.

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting painful neuropathy that occurs commonly during cancer management, which often leads to the discontinuation of medication. Previous studies suggest that the α9α10 nicotinic acetylcholine receptor (nAChR)-specific antagonist αO-conotoxin GeXIVA[1,2] is effective in CIPN models; however, the related mechanisms remain unclear. Here, we analyzed the preventive effect of GeXIVA[1,2] on neuropathic pain in the long-term oxaliplatin injection-induced CIPN model.

Enhancing Stability and Albumin Binding Efficiency of α-Conotoxin GI through Fatty Acid Modification.

α-Conotoxin GI is a competitive blocker of muscle-type acetylcholine receptors and holds the potential for being developed as a molecular probe or a lead compound for drug discovery. In this study, four fatty acid-modified α-conotoxin GI analogues of different lengths were synthesized by using a fatty acid modification strategy. Then, we performed a series of stability assays, albumin binding assays, and pharmacological activity assays to evaluate these modified mutants.

Synthesis, Activity, and Application of Fluorescent Analogs of [D1G, Δ14Q]LvIC Targeting α6β4 Nicotinic Acetylcholine Receptor.

α6β4* nicotinic acetylcholine receptor (nAChR) (* represents the possible presence of additional subunits) is mainly distributed in the central and peripheral nervous system and is associated with neurological diseases, such as neuropathic pain; however, the ability to explore its function and distribution is limited due to the lack of pharmacological tools. As one of the analogs of α-conotoxin (α-CTx) LvIC from , [D1G, Δ14Q]LvIC (Lv) selectively and potently blocks α6/α3β4 nAChR (α6/α3 represents a chimera). Here, we synthesized three fluorescent analogs of Lv by connecting fluorescent molecules 6-carboxytetramethylrhodamine succinimidyl ester (6-TAMRA-SE, R), Cy3 NHS ester (Cy3, C) and BODIPY-FL NHS ester (BDP, B) to the N-terminus of the peptide and obtained Lv-R, Lv-C, and Lv-B, respectively.

Structure-Activity Relationships of Alanine Scan Mutants αO-Conotoxins GeXIVA[1,2] and GeXIVA[1,4].

αO-Conotoxin GeXIVA is a selective α9α10 nicotinic acetylcholine receptor (nAChR) inhibitor displaying two disulfide bonds that can form three isomers. The bead (GeXIVA[1,2]) and ribbon (GeXIVA[1,4]) isomers possess the highest activity on rat and human α9α10 nAChRs. However, the molecular mechanism by which they inhibit the α9α10 nAChR is unknown.

Potential Mechanisms of Metformin-Induced Apoptosis in HeLa Cells.

Metformin is a traditional antidiabetic drug that also shows potential antitumor effects in cervical cancer. However, some of its apoptosis-related mechanisms are still unclear. In this study, flow cytometry, western blotting, and RNA sequencing (RNA-seq) were used to evaluate the molecular mechanisms of metformin in HeLa cells.

Substitution of D-Arginine at Position 11 of α-RgIA Potently Inhibits α7 Nicotinic Acetylcholine Receptor.

Conotoxins are a class of disulfide-rich peptides found in the venom of cone snails, which have attracted considerable attention in recent years due to their potent activity on ion channels and potential for therapeutics. Among them, α-conotoxin RgIA, a 13-residue peptide, has shown great promise as a potent inhibitor of α9α10 nAChRs for pain management. In this study, we investigated the effect of substituting the naturally occurring L-type arginine at position 11 of the RgIA sequence with its D-type amino acid.

Mitogenome Characterization of Four Species and Comparative Analysis.

Cone snails, as a type of marine organism, have rich species diversity. Traditionally, classifications of cone snails were based mostly on radula, shell, and anatomical characters. Because of these phenotypic features' high population variability and propensity for local adaptation and convergence, identifying species can be difficult and occasionally inaccurate.

Molecular Determinants of Species Specificity of α-Conotoxin TxIB towards Rat and Human α6/α3β4 Nicotinic Acetylcholine Receptors.

Conotoxins are widely distributed and important for studying ligand-gated ion channels. TxIB, a conotoxin consisting of 16 amino acids derived from , is a unique selective ligand that blocks rat α6/α3β2β3 nAChR (IC = 28 nM) without affecting other rat subtypes. However, when the activity of TxIB against human nAChRs was examined, it was unexpectedly found that TxIB had a significant blocking effect on not only human α6/α3β2β3 nAChR but also human α6/α3β4 nAChR, with an IC of 537 nM.

Loop2 Size Modification Reveals Significant Impacts on the Potency of α-Conotoxin TxID.

α4/6-conotoxin TxID, which was identified from , simultaneously blocks rat (r) α3β4 and rα6/α3β4 nicotinic acetylcholine receptors (nAChRs) with IC values of 3.6 nM and 33.9 nM, respectively.

Synthesis of the Most Potent Isomer of μ-Conotoxin KIIIA Using Different Strategies.

In the chemical synthesis of conotoxins with multiple disulfide bonds, the oxidative folding process can result in diverse disulfide bond connectivities, which presents a challenge for determining the natural disulfide bond connectivities and leads to significant structural differences in the synthesized toxins. Here, we focus on KIIIA, a μ-conotoxin that has high potency in inhibiting Nav1.2 and Nav1.

Discovery, Characterization, and Engineering of LvIC, an α4/4-Conotoxin That Selectively Blocks Rat α6/α3β4 Nicotinic Acetylcholine Receptors.

α6β4 nicotinic acetylcholine receptors (nAChRs) are expressed in the central and peripheral nervous systems, but their functions are not fully understood, largely because of a lack of specific ligands. Here, we characterized a novel α-conotoxin, LvIC, and designed a series of analogues to probe structure-activity relationships at the α6β4 nAChR. The potency and selectivity of these conotoxins were tested using two-electrode voltage-clamp recording on nAChR subtypes expressed in oocytes.

Peptides from the Sea Anemone with Modified Inhibitor Cystine Knot (ICK) Fold Inhibit Nicotinic Acetylcholine Receptors.

Nicotinic acetylcholine receptors (nAChRs) play an important role in the functioning of the central and peripheral nervous systems, and other organs of living creatures. There are several subtypes of nAChRs, and almost all of them are considered as pharmacological targets in different pathological states. The crude venom of the sea anemone showed the ability to interact with nAChRs.

Novel αO-conotoxin GeXIVA[1,2] Nonaddictive Analgesic with Pharmacokinetic Modelling-Based Mechanistic Assessment.

αO-conotoxin GeXIVA[1,2] was isolated in our laboratory from a snail native to the South China Sea, and is a novel, nonaddictive, intramuscularly administered analgesic targeting the α9α10 nicotinic acetylcholine receptor (nAChR) with an IC of 4.61 nM. However, its pharmacokinetics and related mechanisms underlying the analgesic effect remain unknown.