Two major human diseases caused by filariid nematodes are onchocerciasis, or river blindness, and lymphatic filariasis, which can lead to elephantiasis. The drugs ivermectin, diethylcarbamazine (DEC), and albendazole are used in control programs for these diseases, but are mainly effective against the microfilarial stage and have minimal or no effect on adult worms. Adult Onchocerca volvulus and Brugia malayi worms (macrofilariae) can live for up to 15 years, reproducing and allowing the infection to persist in a population. Therefore, to support control or elimination of these two diseases, effective macrofilaricidal drugs are necessary, in addition to current drugs. In an effort to identify macrofilaricidal drugs, we screened an FDA-approved library with adult worms of Brugia spp. and Onchocerca ochengi, third-stage larvae (L3s) of Onchocerca volvulus, and the microfilariae of both O. ochengi and Loa loa. We found that auranofin, a gold-containing drug used for rheumatoid arthritis, was effective in vitro in killing both Brugia spp. and O. ochengi adult worms and in inhibiting the molting of L3s of O. volvulus with IC50 values in the low micromolar to nanomolar range. Auranofin had an approximately 43-fold higher IC50 against the microfilariae of L. loa compared with the IC50 for adult female O. ochengi, which may be beneficial if used in areas where Onchocerca and Brugia are co-endemic with L. loa, to prevent severe adverse reactions to the drug-induced death of L. loa microfilariae. Further testing indicated that auranofin is also effective in reducing Brugia adult worm burden in infected gerbils and that auranofin may be targeting the thioredoxin reductase in this nematode.

K2P (KCNK) potassium channels generate “leak” potassium currents that strongly influence cellular excitability and contribute to pain, somatosensation, anesthesia, and mood. Despite their physiological importance, K2Ps lack specific pharmacology. Addressing this issue has been complicated by the challenges that the leak nature of K2P currents poses for electrophysiology-based high-throughput screening strategies. Here, we present a yeast-based high-throughput screening assay that avoids this problem. Using a simple growth-based functional readout, we screened a library of 106,281 small molecules and identified two new inhibitors and three new activators of the mammalian K2P channel K2P2.1 (KCNK2, TREK-1). By combining biophysical, structure–activity, and mechanistic analysis, we developed a dihydroacridine analogue, ML67-33, that acts as a low micromolar, selective activator of temperature- and mechano-sensitive K2P channels. Biophysical studies show that ML67-33 reversibly increases channel currents by activating the extracellular selectivity filter-based C-type gate that forms the core gating apparatus on which a variety of diverse modulatory inputs converge. The new K2P modulators presented here, together with the yeast-based assay, should enable both mechanistic and physiological studies of K2P activity and facilitate the discovery and development of other K2P small molecule modulators.

We report the discovery of benzoxaborole antitrypanosomal agents and their structure-activity relationships on central linkage groups and different substitution patterns in the sulfur-linked series. The compounds showed in vitro growth inhibition IC 50 values as low as 0.02 μg/mL and in vivo efficacy in acute murine infection models against Tryapnosoma brucei.

Human African trypanosomiasis (HAT, commonly known as African sleeping sickness) is categorized as a neglected disease, as it afflicts > 50,000 people annually in sub-saharan Africa, and there are few formal programs in the world focused on drug discovery approaches for this disease. In this study, we examined the crude extracts of two fungal strains (Aspergillus fumigatus and Nectria inventa) isolated from deep water sediment which provided >99% growth inhibition at 1 μg/mL of Trypanosoma brucei, the causative parasite of HAT. A collection of fifteen natural products was supplemented with six semi-synthetic derivatives and one commercially available compound. Twelve of the compounds, each containing a diketopiperazine core, showed excellent activity against T. brucei (IC50 = 0.002 - 40 μM), with selectivity over mammalian cells as great as 20-fold. The trypanocidal diketopiperazines were also tested against two cysteine protease targets Rhodesain and TbCatB, where five compounds showed inhibition activity at concentrations less than 20 μM. A preliminary activity pattern is described and analyzed.

Human African trypanosomiasis (HAT), also known as African sleeping sickness, is a neglected tropical disease with inadequate therapeutic options. We have launched a collaborative new lead discovery venture using our repository of extracts and natural product compounds as input into our growth inhibition primary screen against Trypanosoma brucei. Careful evaluation of the spectral data of the natural products and derivatives allowed for the elucidation of the absolute configuration (using the modified Mosher's method) of two new peroxiterpenes: (+)-muqubilone B (1a) and (−)-ent-muqubilone (3a). Five known compounds were also isolated: (+)-sigmosceptrellin A (4a), (+)-sigmosceptrellin A methyl ester (4b), (−)-sigmosceptrellin B (5), (+)-epi-muqubillin A (6) and (−)-epi-nuapapuin B methyl ester (7). The isolated peroxiterpenes demonstrated activities in the range from IC 50 = 0.2 -2 μg/mL.The search for chemotherapeutics to treat human African trypanosomiasis (HAT), also known as African sleeping sickness, has not been a major target of industry drug discovery campaigns, even though the currently available therapeutics are inadequate.1 This is surprising as there are 50,000 annual cases of infection, HAT is the world's third most devastating parasitic disease, and it remains a major threat to more than 60 million people.2 -4 Because it is a serious health problem for resource poor regions of Africa, HAT is designated as a neglected tropical disease (NTD). The causative agent is a protozoan parasite, Trypanosoma brucei, 5 subdivided in two sub-genera, T. brucei gambiense in West Africa and T. brucei rhodesiense in East Africa. 1 Most of the four current chemotherapeutics to combat these parasites at their different development stages are very antiquated. The drugs (by registration date for HAT treatment) consist of suramin4 (1922), pentamidine1 (1941), melarsoprol3 (1949), and eflorithine1 (1990). Another relevant point is that new strains of T. brucei are showing cross-resistance to some of these agents.6 In recent years, only one compound, DB289 7 (a synthetic analog of pentamidine), received serious clinical evaluation against HAT, but further development was discontinued in 2008. 3 * To whom correspondence should be addressed. phil@chemistry.ucsc.edu. Tel: (831)