No abstract

Chagas disease, a neglected illness, affects nearly 12-14 million people in endemic areas of Latin America. Although the occurrence of acute cases sharply has declined due to Southern Cone Initiative efforts to control vector transmission, there still remain serious challenges, including the maintenance of sustainable public policies for Chagas disease control and the urgent need for better drugs to treat chagasic patients. Since the introduction of benznidazole and nifurtimox approximately 40 years ago, many natural and synthetic compounds have been assayed against Trypanosoma cruzi, yet only a few compounds have advanced to clinical trials. This reflects, at least in part, the lack of consensus regarding appropriate in vitro and in vivo screening protocols as well as the lack of biomarkers for treating parasitaemia. The development of more effective drugs requires (i) the identification and validation of parasite targets, (ii) compounds to be screened against the targets or the whole parasite and (iii) a panel of minimum standardised procedures to advance leading compounds to clinical trials. This third aim was the topic of the workshop entitled Experimental Models in Drug Screening and Development for Chagas Disease, held in Rio de Janeiro, Brazil, on the 25th and 26th of November 2008 by the Fiocruz Program for Research and Technological Development on Chagas Disease and Drugs for Neglected Diseases Initiative. During the meeting, the minimum steps, requirements and decision gates for the determination of the efficacy of novel drugs for T. cruzi control were evaluated by interdisciplinary experts and an in vitro and in vivo flowchart was designed to serve as a general and standardised protocol for screening potential drugs for the treatment of Chagas disease

These findings contribute to evidence identifying the σ(1) receptor as a modulator of activity-induced spinal sensitization and pain hypersensitivity, and suggest σ(1) receptor antagonists as potential novel treatments for neuropathic pain.

Coibamide A (1) is a new, potent antiproliferative depsipeptide which was isolated from a marine Leptolyngbya cyanobacterium collected from the Coiba National Park, Panama. The planar structure of 1 was elucidated by a combination of NMR spectroscopy and mass spectrometry. Exhaustive 1D and 2D NMR spectroscopy included natural abundance 15 N and variable temperature experiments; mass spectrometry included TOF-ESI-MS n and FT-MS n experiments. Chemical degradation followed by chiral HPLC-and GC-MS analyses was used to assign the absolute configuration of 1. This highly methylated cyclized depsipeptide exhibited an unprecedented selectivity profile in the NCI 60 cancer cell line panel and appears to act via a novel mechanism.Marine organisms continue to yield a diverse array of biologically active molecules, a remarkable number of which are peptide-based cancer cell toxins of putative microbial symbiont biogenesis. 1 Development of these as anticancer drugs has met with some success: 2 ascidian-derived dihydrodidemnin B (aplidin®) has orphan drug status for the treatment of multiple myeloma and acute lymphoblastic leukemia; green algal isolate kahalalide F, and TZT-1027, a synthetic analog of the cyanobacterial metabolite dolastatin 10, reached phase II clinical trials. Other important cyanobacterial peptide leads include the cryptophycins and curacin A, 3 and these organisms continue to produce a wealth of anticancer lead compounds. 4 The high degree of N-methylation of many of these cyanobacterial peptides may improve their druggability since N-methylation has been shown to improve pharmacological parameters such as lipophilicity, proteolytic stability and duration of action, properties for which regular peptides are notoriously poor and which limits their bioavailability. 5In the context of our International Cooperative Biodiversity Groups program (ICBG) based in Panama, which focuses on drug discovery, biodiversity conservation and sustainable economic growth, we have isolated a potent cancer cell toxin with an unprecedented selectivity profile in the NCI 60 cell line panel. This cyanobacterial depsipeptide, named coibamide A in tribute