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Chagas disease and Leishmaniasis are neglected endemic protozoan diseases recognized as public health problems by the World Health Organization. These diseases affect millions of people around the world however, efficient and low-cost treatments are not available. Different steroid molecules with antimicrobial and antiparasitic activity were isolated from diverse organisms (ticks, plants, fungi). These molecules have complex structures that make de novo synthesis extremely difficult. In this work, we designed new and simpler compounds with antiparasitic potential inspired in natural steroids and synthesized a series of nineteen steroidal arylideneketones and thiazolidenehydrazines. We explored their biological activity against Leishmania infantum, Leishmania amazonensis, and Trypanosoma cruzi in vitro and in vivo. We also assayed their genotoxicity and acute toxicity in vitro and in mice. The best compound, a steroidal thiosemicarbazone compound 8 (ID_1260) was active in vitro (IC50 200 nM) and in vivo (60% infection reduction at 50 mg/kg) in Leishmania and T. cruzi. It also has low toxicity in vitro and in vivo (LD50 >2000 mg/kg) and no genotoxic effects, being a promising compound for anti-trypanosomatid drug development.

The trypanosomatid parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania are the causative agents of human African trypanosomiasis, Chagas Disease and Leishmaniasis, respectively. These infections primarily affect poor, rural communities in the developing world, and are responsible for trapping sufferers and their families in a disease/poverty cycle. The development of new chemotherapies is a priority given that existing drug treatments are problematic. In our search for novel anti-trypanosomatid agents, we assess the growth-inhibitory properties of >450 compounds from in-house and/or “Pathogen Box” (PBox) libraries against L. infantum, L. amazonensis, L.braziliensis, T. cruzi and T. brucei and evaluate the toxicities of the most promising agents towards murine macrophages. Screens using the in-house series identified 17 structures with activity against and selective toward Leishmania: Compounds displayed 50% inhibitory concentrations between 0.09 and 25 μM and had selectivity index values >10. For the PBox library, ~20% of chemicals exhibited anti-parasitic properties including five structures whose activity against L. infantum had not been reported before. These five compounds displayed no toxicity towards murine macrophages over the range tested with three being active in an in vivo murine model of the cutaneous disease, with 100% survival of infected animals. Additionally, the oral combination of three of them in the in vivo Chagas disease murine model demonstrated full control of the parasitemia. Interestingly, phenotyping revealed that the reference strain responds differently to the five PBox-derived chemicals relative to parasites isolated from a dog. Together, our data identified one drug candidate that displays activity against Leishmania and other Trypanosomatidae in vitro and in vivo, while exhibiting low toxicity to cultured mammalian cells and low in vivo acute toxicity.

When two similar species co-occur in time and space, strong mechanisms isolating them from each other are expected. Acanthoscurria suina Pocock, 1903 and Eupalaestrus weijenberghi (Thorell, 1894) are two sympatric and synchronic tarantulas that inhabit burrows in Uruguay's meadows. Here we test how and when reproductive isolation operates between these species. We exposed females of each species simultaneously to two males: either one male of each species, or two males of the same species. Males courted females of both species. Contrary to expectations, however, females of A. suina responded more effusively to heterospecific than to conspecific males, whereas females of E. weijenberghi only responded to conspecific males. Clasping (prelude of mating) was only recorded for couples of the same species. Females of A. suina at first seem to prefer the stronger body vibrations performed by heterospecific courting males than by males of their own species. [PUBLICATION ABSTRACT]

A series of fifty arylideneketones and thiazolidenehydrazines was evaluated against Leishmania infantum and Leishmania braziliensis. Furthermore, new simplified thiazolidenehydrazine derivatives were evaluated against Trypanosoma cruzi. The cytotoxicity of the active compounds on non-infected fibroblasts or macrophages was established in vitro to evaluate the selectivity of their anti-parasitic effects. Seven thiazolidenehydrazine derivatives and ten arylideneketones had good activity against the three parasites. The IC50 values for T. cruzi and Leishmania spp. ranged from 90 nM–25 µM. Eight compounds had multi-trypanocidal activity against T. cruzi and Leishmania spp. (the etiological agents of cutaneous and visceral forms). The selectivity of these active compounds was better than the three reference drugs: benznidazole, glucantime and miltefosine. They also had low toxicity when tested in vivo on zebrafish. Trying to understand the mechanism of action of these compounds, two possible molecular targets were investigated: triosephosphate isomerase and cruzipain. We also used a molecular stripping approach to elucidate the minimal structural requirements for their anti-T. cruzi activity.

Arising from: S. N. Gorb et al. Nature443, 407 (2006)10.1038/443407a ; Gorb et al. reply As with all spiders, tarantulas spin silk from specialized structures in the abdomen called spinnerets, which are key features unique to the group. Recently Gorb et al. 1 reported that the zebra tarantula Aphonopelma seemanni also secretes silk from its feet, which might improve its ability to climb on vertical surfaces. Here we show that when the spinnerets are experimentally sealed, the zebra tarantula cannot secrete silk or similar threads, disagreeing with previous reports by Gorb et al. 1 . Additional evidence also disagrees with leg secretion of silk.

The ability of Grammostola. mollicoma (Ausserer 1875) spiderlings (Araneae, Theraphosidae) to emerge from the cocoon without the assistance of their mother was tested experimentally. We created two experimental groups with 23 cocoons in each group. In one of the groups we cut the cocoon wall creating an opening; in the other group, the cocoon remained untouched. We found no differences between the groups in either the number or instar composition of the spiderlings that emerged. The spiderlings were able to emerge without the assistance of their mother. The emerging instars in both groups were precocious compared to previous suggestions in the literature.

The ability of Grammostola. mollicoma (Ausserer 1875) spiderlings (Araneae, Theraphosidae) to emerge from the cocoon without the assistance of their mother was tested experimentally. We created two experimental groups with 23 cocoons in each group. In one of the groups we cut the cocoon wall creating an opening; in the other group, the cocoon remained untouched. We found no differences between the groups in either the number or instar composition of the spiderlings that emerged. The spiderlings were able to emerge without the assistance of their mother. The emerging instars in both groups were precocious compared to previous suggestions in the literature.

The presence of conspicuous, dense scopulae with spatulated setae on the ventral surface of tarsi andmetatarsi of all tarantulas seemsincompatible with the presence of spinning spigots in a lower layer, because scopula setae might interfere with silk release. A 192, 1223-1232 (2006). doi:10.1038/nature08404 Gorb et al. reply Replying to: F. Pérez-Miles, A. Panzera, D. Ortiz-Villatoro & C. Perdomo Nature 461, doi:10.1038/nature08404 (2009) The data presented by Pérez-Miles et al.1 call into question the production of tarantula tarsal silk2, but there remains substantive evidence that would seem to contradict their assertion that tarsal silk is solely due to abdominal silk entangled on to hind legs. Furthermore, scanning electron microscopy examination of tarsal silk reveals a distinct broad area at the beginning of the fibre that we interpret as an initial fluid (see Fig. 1).

Using the road tarantula Eupalaestrus weijenberghi (Thorell 1894), we tested the importance of the third pair of legs in male courtship behavior. Our results showed that the third pair of legs is essential for males to elicit female sexual receptivity. Males with their second pair of legs immobilized elicited receptive responses from females, but males with the third legs immobilized did not. The potential role of the third pair of legs in the generation and/or transmission of seismic signals via the substrate is discussed.