Significance: The α9α10 nicotinic AChR (nAChR) subtype is a recently identified target for the development of breast cancer chemotherapeutics and analgesics, particularly to treat neuropathic pain. Structure/function analyses of antagonists of this subtype are therefore essential for the development of specific therapeutic compounds. TheConusgenus is a rich source of pharmacologically active peptides, and we report here that the αO-conotoxin GeXIVA is a potent and selective antagonist of the α9α10 nAChR subtype. GeXIVA displays unique structural properties among otherConuspeptides and represents a previously unidentified template for molecules active against neuropathic pain.

This study was performed to discover and characterize the first potent α3β2‐subtype‐selective nicotinic acetylcholine receptor (nAChR) ligand. A novel α4/7‐conotoxin, α‐CTxLvIA, was cloned from Conus lividus. Its pharmacological profile at Xenopus laevis oocyte‐expressed rat nAChR subtypes was determined by 2‐electrode voltage‐clamp electrophysiology, and its 3‐dimensional (3D) structure was determined by NMR spectroscopy. α‐CTx LvIA is a 16‐aa C‐terminallyamidated peptide with 2‐disulfide bridges. Using rat subunits expressed in Xenopus oocytes, we found the highest affinity of α‐CTxLvIA was for α3β2 nAChRs (IC ₅₀ 8.7 nM), where blockade was reversible within 2 min. IC ₅₀ values were >100 nM at α6/α3β2β3, α6/α3β4, and α3β4 nAChRs, and ≥3 μM at all other subtypes tested. α3β2 vs. α6β2 subtype selectivity was confirmed for human‐subunit nAChRs with much greater preference (300‐fold) for α3β2 over α6β2 nAChRs. This is the first α‐CTx reported to show high selectivity for human α3β2 vs. α6β2 nAChRs. α‐CTxLvIA adopts two similarly populated conformations water: one (assumed to be bioactive) is highly structured, whereas the other is mostly random coil in nature. Selectivity differences with the similarly potent, but less selective, α3β2 nAChR antagonist α‐CTx PeIA probably reside within the three residues, which differ in loop 2, given their otherwise similar 3D structures. α4/7‐CTx LvIA is a new, potent, selective α3β2 nAChR antagonist, which will enable detailed studies of α3β2 nAChR structure, function, and physiological roles.—Luo, S., Zhangsun, D., Schroeder, C. I., Zhu, X., Hu, Y., Wu, Y., Weltzin, M. M., Eberhard, S., Kaas, Q., Craik, D. J., McIntosh, J. M., Whiteaker, P. A novel α4/7‐conotoxin LvIA from Conus lividus that selectively blocks α3β2 vs. α6/α3β2β3 nicotinic acetylcholine receptors. FASEB J. 28, 1842–1853 (2014). www.fasebj.org

Oxaliplatin is a third-generation platinum drug and is widely used as a first-line therapy for the treatment of colorectal cancer (CRC). However, a large number of patients receiving oxaliplatin develop dose-limiting painful neuropathy. Here, we report that αO-conotoxin GeXIVA[1,2], a highly potent and selective antagonist of the α9α10 nicotinic acetylcholine receptor (nAChR) subtype, can relieve and reverse oxaliplatin-induced mechanical and cold allodynia after single and repeated intramuscular (IM) injections in rats. Treatments were started at 4 days post oxaliplatin injection when neuropathic pain emerged and continued for 8 and 16 days. Cold score and mechanical paw withdrawal threshold (PWT) were detected by the acetone test and von Frey test respectively. GeXIVA[1,2] significantly relieved mechanical and cold allodynia in oxaliplatin-treated rats after a single injection. After repeated treatments, GeXIVA[1,2] produced a cumulative analgesic effect without tolerance and promoted recovery from neuropathic pain. Moreover, the long lasting analgesic effect of GeXIVA[1,2] on mechanical allodynia continued until day 10 after the termination of the 16-day repeated treatment procedure. On the contrary, GeXIVA[1,2] did not affect acute mechanical and thermal pain behaviors in normal rats after repeated injections detected by the von Frey test and tail flick test. GeXIVA[1,2] had no influence on rat hind limb grip strength and body weight after repeated treatments. These results indicate that αO-conotoxin GeXIVA[1,2] could provide a novel strategy to treat chemotherapy-induced neuropathic pain.

Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder characterized by cognitive impairments such as memory loss and executive dysfunction. The primary pathological features of AD include the deposition of amyloid-beta (Aβ) plaques, the hyperphosphorylation of tau proteins leading to neurofibrillary tangles, disruptions of neuronal and synaptic functions, and chronic inflammatory responses. These multifactorial interactions drive disease progression. To date, various therapeutic agents targeting these pathological mechanisms have been developed. This article provides a comprehensive review of the pathogenesis of AD, recent advances in drug development targeting different pathways, current challenges, and future directions, aiming to offer valuable insights for clinical treatment and research.

α6β2 Nicotinic acetylcholine receptors (nAChRs) expressed by dopaminergic neurons in the CNS are potential therapeutic targets for the treatment of several neuropsychiatric diseases, including nicotine addiction and Parkinson disease. However, recent studies indicate that the α6 subunit can also associate with the β4 subunit to form α6β4 nAChRs that are difficult to pharmacologically distinguish from α6β2, α3β4, and α3β2 subtypes. The current study characterized a novel 16-amino acid α-conotoxin (α-CTx) TxIB from Conus textile whose sequence is GCCSDPPCRNKHPDLC-amide as deduced from gene cloning. The peptide and an analog with an additional C-terminal glycine were chemically synthesized and tested on rat nAChRs heterologously expressed in Xenopus laevis oocytes. α-CTx TxIB blocked α6/α3β2β3 nAChR with an IC₅₀ of 28 nm. In contrast, the peptide showed little or no block of other tested subtypes at concentrations up to 10 μm. The three-dimensional solution structure of α-CTx TxIB was determined using NMR spectroscopy. α-CTx TxIB represents a uniquely selective ligand for probing the structure and function of α6β2 nAChRs.

Six plasmids carrying a snowdrop lectin ( agglutinin, GNA) and one of three selection markers were successfully transferred into two sugarcane cultivars (FN81–745 and Badila) via -mediated transformation. strains LBA4404, EHA105 and A281 that harboured a super-binary vector were used for sugarcane transformation. The use of the hygromycin (Hyg) resistance gene (), phosphinothrincin (PPT) resistance gene () or G418 resistance gene () as a screenable marker facilitated the initial selection of GNA transgenic sugarcane callus with different efficiencies and helped the rapid segregation of individual transformation events. All the three selective marker genes were controlled by CaMV 35S promoter, while GNA gene was controlled by promoter of RSs-1 (rice sucrose synthase-1) or Ubi (maize ubiquitin). Factors important to successful transformation mediated by were optimized, which included concentration of , medium composition, co-cultivated methods with plant tissue, strain virulence and different selective marker genes. An efficient protocol for sugarcane transformation mediated by was established. The GNA gene has been integrated into sugarcane genome as demonstrated by PCR and Southern dot blotting detections. The preliminary results from bioassay demonstrated a significant resistance of the transgenic sugarcane plants to woolly aphid ( Zehnther) indicating thus the possibility for obtaining a transgenic sugarcane cultivar with resistance to woolly aphid.