Octopamine signaling in the metazoan pathogen Schistosoma mansoni: localization, small-molecule screening and opportunities for drug development.
El-Sakkary N, Chen S, Arkin MR, Caffrey CR, Ribeiro P.
Disease Models & Mechanisms, 2018 Jul 30;11(7)
In a recent interview to Disease Models & Mechanisms, Nelly El-Sakkary talks about discovery of neurotransmitter octopamine in the parasitic flatworm, Schistosoma, where it plays an important role in controlling worm movement. In collaboration between the CDIPD, Small-Molecule Discovery Center at UCSF, and laboratory of Paula Ribeiro at McGill University, the researchers tested different neurotransmitters and modulators of these neurotransmitter signaling pathways on parasites. Octopamine and related neurotransmitters all caused a pronounced increase in movement. The reseachers also used laser microscopy to map the nervous system, localize octopamine throughout the nervous system and to determine that the flatworm brain is made up of four distinct lobes, rather than two lobes as was previously reported.
Twenty five years of drug discovery at the University of California targeting Kinetoplastid parasites.
McKerrow JH, Siqueira-Neto JL, McCall L-I and Otrubova K
Journal of Pharmaceutics & Drug Development, 2016, Vol. 4, Issue 1
This review summarizes 25 years of screening compounds against three major kinetoplastid parasites, Trypanosoma brucei, Trypanosoma cruzi, and Leishmania spp. The work was carried out at two University of California campuses by a consortium of scientists. The history of this effort is summarized beginning with DARPA and NIAID TDRU projects. The compound collections that were screened came from both academic and industry sources. To facilitate screening, high throughput or high content microtiter plate-based assays were developed. Three approaches to discovery of new drugs for kinetoplastid diseases are presented. These include structure-based drug design against specific parasite molecular targets, repurposing of already approved drugs, and screening of marine natural products. As similar screening efforts against other molecular targets or with other compound libraries are ongoing, one conclusion is that the current bottleneck in drug development for neglected tropical diseases is downstream of compound screening and hit to lead. More medicinal chemistry efforts for lead optimization and more preclinical package work needs to be done.
X-ray structures of thioredoxin and thioredoxin reductase from Entamoeba histolytica and prevailing hypothesis of the mechanism of Auranofin action.
Parsonage D, Sheng F, Hirata K, Debnath A, McKerrow JH, Reed SL, Abagyan R, Poole LB, Podust LM.
J. Struct. Biol. 2016 May;194(2):180-90.
The anti-arthritic gold-containing drug Auranofin is lethal to the protozoan intestinal parasite Entamoeba histolytica, the causative agent of human amebiasis, in both culture and animal models of the disease. A putative mechanism of Auranofin action proposes that monovalent gold, Au(I), released from the drug, can bind to the redox-active dithiol group of thioredoxin reductase (TrxR). Au(I) binding in the active site is expected to prevent electron transfer to the downstream substrate thioredoxin (Trx), thus interfering with redox homeostasis in the parasite. To clarify the molecular mechanism of Auranofin action in more detail, we determined a series of atomic resolution X-ray structures for E. histolytica thioredoxin (EhTrx) and thioredoxin reductase (EhTrxR), the latter with and without Auranofin. Only the disulfide-bonded form of the active site dithiol (Cys(140)-Cys(143)) was invariably observed in crystals of EhTrxR in spite of the addition of reductants in various crystallization trials, and no gold was found associated with these cysteines. Non-catalytic Cys(286) was identified as the only site of modification, but further mutagenesis studies using the C286Q mutant demonstrated that this site was not responsible for inhibition of EhTrxR by Auranofin. Interestingly, we obtained both of the catalytically-relevant conformations of this bacterial-like, low molecular weight TrxR in crystals without requiring an engineered disulfide linkage between Cys mutants of TrxR and Trx (as was originally done with Escherichia coli TrxR and Trx). We note that the -CXXC- catalytic motif, even if reduced, would likely not provide space sufficient to bind Au(I) by both cysteines of the dithiol group.