No abstract

Chinese tree shrews (Tupaia belangeri chinensis) possess many features valuable in animals used as experimental models in biomedical research. Currently, there are numerous attempts to employ tree shrews as models for a variety of human disorders: depression, myopia, hepatitis B and C virus infections, and hepatocellular carcinoma, to name a few. Here we present a publicly available annotated genome sequence for the Chinese tree shrew. Phylogenomic analysis of the tree shrew and other mammalians highly support its close affinity to primates. By characterizing key factors and signalling pathways in nervous and immune systems, we demonstrate that tree shrews possess both shared common and unique features, and provide a genetic basis for the use of this animal as a potential model for biomedical research.

Peptidomics and genomics analyses were used to study an anti-infection array of peptides of amphibian skin. 372 cDNA sequences of antimicrobial peptides were characterized from a single individual skin of the frog Odorrana grahami that encode 107 novel antimicrobial peptides. This contribution almost triples the number of currently reported amphibian antimicrobial peptides. The peptides could be organized into 30 divergent groups, including 24 novel groups. The diversity in peptide coding cDNA sequences is, to our knowledge, the most extreme yet described for any animal. The patterns of diversification suggest that point mutations as well as insertion, deletion, and "shuffling" of oligonucleotide sequences were responsible for the diversity. The diversity of antimicrobial peptides may have resulted from the diversity of microorganisms. These diverse peptides exhibited both diverse secondary structure and "host defense" properties.

Summary The capsaicin receptor TRPV1 ion channel is a polymodal nociceptor that responds to heat with exquisite sensitivity through an unknown mechanism. Here we report the identification of a toxin, RhTx, from the venom of Chinese red-headed centipede that potently activates TRPV1 to produce excruciating pain. RhTx is a 27-amino acid small peptide that forms a compact polarized molecule with very rapid binding kinetics and high affinity for TRPV1. We show that RhTx targets the channel’s heat activation machinery to cause powerful activation at normal body temperature. The RhTx-TRPV1 interaction is mediated by the toxin’s highly charged C-terminus, which associates tightly to the charge-rich outer pore region of the channel where it can directly interact with the pore helix and turret. These findings demonstrate that RhTx binding to the outer pore can induce TRPV1 heat activation, therefore providing crucial new structural information on the heat activation machinery.

The emergence of carbapenem-resistantAcinetobacter baumanniiandPseudomonas aeruginosaraises fears of untreatable infections and poses the greatest health threats. Antimicrobial peptides (AMPs) are regarded as the most ideal solution to this menace. In this study, a set of peptides was designed based on our previously reported peptide cathelicidin-BF-15, and the lead peptide ZY4, a cyclic peptide stabilized by a disulfide bridge with high stability in vivo (the half-life is 1.8 h), showed excellent activity againstP. aeruginosaandA. baumannii, including standard and clinical multidrug-resistant (MDR) strains. ZY4 killed bacteria by permeabilizing the bacterial membrane and showed low propensity to induce resistance, exhibited biofilm inhibition and eradication activities, and also killed persister cells. Notably, administration of ZY4 decreased susceptibility to lung infection byP. aeruginosaand suppressed dissemination ofP. aeruginosaandA. baumanniito target organs in a mouse septicemia infection model. These findings identify ZY4 as an ideal candidate against MDR bacterial infections.

Loss-of-function mutations in the human voltage-gated sodium channel Na V 1.7 result in a congenital indifference to pain. Selective inhibitors of Na V 1.7 are therefore likely to be powerful analgesics for treating a broad range of pain conditions. Herein we describe the identification of μ-SLPTX-Ssm6a, a unique 46-residue peptide from centipede venom that potently inhibits Na V 1.7 with an IC 50 of ∼25 nM. μ-SLPTX-Ssm6a has more than 150-fold selectivity for Na V 1.7 over all other human Na V subtypes, with the exception of Na V 1.2, for which the selectivity is 32-fold. μ-SLPTX-Ssm6a contains three disulfide bonds with a unique connectivity pattern, and it has no significant sequence homology with any previously characterized peptide or protein. μ-SLPTX-Ssm6a proved to be a more potent analgesic than morphine in a rodent model of chemicalinduced pain, and it was equipotent with morphine in rodent models of thermal and acid-induced pain. This study establishes μ-SPTX-Ssm6a as a promising lead molecule for the development of novel analgesics targeting Na V 1.7, which might be suitable for treating a wide range of human pain pathologies.chronic pain | drug discovery | peptide therapeutic

Centipedes are excellent predatory arthropods that inject venom to kill or immobilize their prey. Although centipedes have long been known to be venomous, their venoms remain largely unexplored. The chemical components responsible for centipede predation and the functional mechanisms are unknown. Twenty-six neurotoxin-like peptides belonging to ten groups were identified from the centipede venoms, Scolopendra subspinipes mutilans L. Koch by peptidomics combined with transcriptome analysis, revealing the diversity of neurotoxins. These neurotoxins each contain two to four intramolecular disulfide bridges, and in most cases the disulfide framework is different from that found in neurotoxins from the venoms of spiders, scorpions, marine cone snails, sea anemones, and snakes (5S animals). Several neurotoxins contain potential insecticidal abilities, and they are found to act on voltage-gated sodium, potassium, and calcium channels, respectively. Although these neurotoxins are functionally similar to the disulfiderich neurotoxins found in the venoms of 5S animals in that they modulate the activity of voltage-gated ion channels, in almost all cases the primary structures of the centipede venom peptides are unique. This represents an interesting case of convergent evolution in which different venomous animals have evolved different molecular strategies for targeting the same ion channels in prey and predators. Moreover, the high level of biochemical diversity revealed in this study suggests that centipede venoms might be attractive subjects for prospecting and screening for peptide candidates with potential pharmaceutical or agrochemical applications. Molecular & Cellular

Horseflies are economically important blood-feeding arthropods and also a nuisance for humans and vectors for filariasis. They rely heavily on the pharmacological properties of their saliva to get a blood meal and suppress immune reactions of hosts. Little information is available on antihemostatic substances in horsefly salivary glands; especially no horsefly immune suppressants have been reported. By proteomics or peptidomics and coupling transcriptome analysis with pharmacological testing, several families of proteins or peptides, which act mainly on the hemostatic system or immune system of the host, were identified and characterized from 30,000 pairs salivary glands of the horsefly Tabanus yao (Diptera, Tabanidae). They are: (i) a novel family of inhibitors of platelet aggregation including two members, which possibly inhibit platelet aggregation by a novel mechanism and act on platelet membrane, (ii) a novel family of immunosuppressant peptides including 12 members, which can inhibit interferon-␥ production and increase interleukin-10 secretion, (iii) a serine protease inhibitor with 56 amino acid residues containing anticoagulant activity, (iv) a serine protease with anticoagulant activity, (v) a protease with fibrinogenolytic activity, (vi) three families of antimicrobial peptides including six members, (vii) a hyaluronidase, (viii) a vasodilator peptide, which is an isoform of vasotab identified from Hybomitra bimaculata, and interestingly (ix) two metallothioneins, which are the first metallothioneins reported from invertebrate salivary glands. The current work will facilitate the understanding of the molecular mechanisms of the ectoparasite-host relationship and help in identifying novel vaccine targets and novel leading pharmacological compounds. Molecular & Cellular Proteomics 7:582-590, 2008.