Active natural product scaffolds against trypanosomatid parasites : a review

This work was supported through funding from the EPSRC and the School of Chemistry (University of St Andrews).Neglected tropical diseases caused by trypanosomatid parasites are a continuing and escalating problem, which devastate the less economically developed cultures in countries in which they are endemic by impairing both human and animal health. Current drugs for these diseases are regarded as out-of-date and expensive, with unacceptable side-effects and mounting parasite resistance, meaning there is an urgent need for new therapeutics. Natural products have long been a source of potent, structurally diverse bioactive molecules. Herein are reviewed natural products with reported trypanocidal activity, which have been clustered based on core structural similarities, to aid the future discovery of new trypanocidal core motifs with potential routes to synthetically accessible natural product cores suggested.PostprintPeer reviewe

Convenient synthesis of alternatively bridged tryptophan ketopiperazines and their activities against trypanosomatid parasites

This work was supported through funding from the EPSRC (grant number EP/J500549/1) and the University of St Andrews School of Chemistry.There is an urgent need for the development of new treatments against trypanosomatid parasites; the causative agents of some of the most debilitating diseases in the developing world. This work targets an interesting 6-5-6-6 fused carboline scaffold, accessing a range of substituted derivatives through stereospecific intramolecular Pictet-Spengler condensation. Modification of the cyclisation conditions allowed retention of the carbamate protecting group and gave insight into the reaction mechanism. Compounds' bioactivities were measured against T. brucei, T. cruzi, L. major and HeLa cells. We have identified promising pan-trypanocidal lead compounds based on the core scaffold, and highlight key SAR trends which will be useful for the future development of these compounds as potent trypanocidal agents.PostprintPeer reviewe

Halogenated tryptophan derivatives disrupt essential transamination mechanisms in bloodstream form Trypanosoma brucei

Funding for this work was provided by the University of St Andrews; EPSRC: EP/J500549/1 (TKS); University of Glasgow (MPB); BBSRC: BB/N007999/1 (MPB); Wellcome: 104111/Z/14/Z.Amino acid metabolism within Trypanosoma brucei, the causative agent of human African trypanosomiasis, is critical for parasite survival and virulence. Of these metabolic processes, the transamination of aromatic amino acids is one of the most important. In this study, a series of halogenated tryptophan analogues were investigated for their anti-parasitic potency. Several of these analogues showed significant trypanocidal activity. Metabolomics analysis of compound-treated parasites revealed key differences occurring within aromatic amino acid metabolism, particularly within the widely reported and essential transamination processes of this parasite.Publisher PDFPeer reviewe

Flowering Time

Adaptation genes have a major role to play in the response of plants to environmental changes. Flowering time is a key adaptive trait, responding to environmental and endogenous signals that ensure reproductive growth and devel- opment occurs under favorable environmental conditions. Under a climate change scenario, temperature and water conditions are forecast to change and/or fluctuate, while photoperiods will remain constant at any given latitude. By assessing the current knowledge of the flowering-time pathways in both model (Arabidopsis thaliana) and key cereal (rice, barley, wheat, maize), temperate forage and biofuel grasses (perennial ryegrass, Miscanthus, sugarcane), root (sugar beet), and tree (poplar) crop species, it is possible to define key breeding targets for promoting adaptation and yield stability under future climatic conditions. In Arabidopsis, there are four pathways controlling flowering time, and the genetic and/or epigenetic control of many of the steps in these pathways has been well characterized. Despite A.R. Bentley • I.J. Mackay • E. Mutasa-Go ¨ttgens • J. Cockram (*) The John Bingham Laboratory, NIAB, Huntingdon Road, Cambridge CB3 0LE, UK e-mail: [email protected] E.F. Jensen • I.P. Armstead • C. Hayes • D. Thorogood • A. Lovatt Institute of Grassland and Environmental Research, Plas Gogerddan, Aberystwyth SY23 3EB, UK H. Ho ¨nicka • M. Fladung Johann Heinrich von Thu ¨nen Institute, Institute of Forest Genetics, Sieker Landstr. 2, 22927 Grosshansdorf, Germany K. Hori • M. Yano National Institute of Agrobiological Sciences, 2-1-2 Kannondai, Tsukuba, Ibaraki 305-8602, Japan J.E. Mullet Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, USA R. Morris • N. Pullen Computational and Systems Biology Department, John Innes Centre, Norwich Research Park, Colney, Norwich NR4 7UH, UK C. Kole (ed.), Genomics and Breeding for Climate-Resilient Crops, Vol. 2, DOI 10.1007/978-3-642-37048-9_1, © Springer-Verlag Berlin Heidelberg 2013 1 this, even in this model species, there is little published information on the molecu- lar basis of adaptation to the environment. In contrast, in crop and tree species, flowering time has been continually selected, either directly or indirectly as breeders and growers have selected the material that best suits a particular location. Understanding the genetic basis of this adaptive selection is now being facilitated via cloning of major genes, the mapping of QTL, and the use of marker-assisted breeding for specific flowering targets. In crop species where the genetic basis of flowering is not well understood (i.e., in the emerging biofuel grass, Miscanthus), such work is in its infancy. In cases where the genetic basis is well established, however, there are still grounds for important discovery, via new and emerging methods for mapping and selecting for flowering-time traits (i.e., QTL mapping in MAGIC populations, RABID selection), as well as methods for creating new genetic combinations with potentially novel flowering-time phenotypes (i.e., via targeted mutagenesis). In the future it is likely that computational modeling approaches which incorporate gene networks and the range of phenological response to measurable environmental conditions will play a central role in predicting the resilience of crop and tree species under climate change scenarios.Peer reviewe

Identification of novel quantitative trait loci for days to ear emergence and flag leaf glaucousness in a bread wheat (Triticum aestivum L.) population adapted to southern Australian conditions

In southern Australia, where the climate is predominantly Mediterranean, achieving the correct flowering time in bread wheat minimizes the impact of in-season cyclical and terminal drought. Flag leaf glaucousness has been hypothesized as an important component of drought tolerance but its value and genetic basis in locally adapted germplasm is unknown. From a cross between Kukri and RAC875, a doubled-haploid (DH) population was developed. A genetic linkage map consisting of 456 DArT and SSR markers was used to detect QTL affecting time to ear emergence and Zadoks growth score in seven field experiments. While ear emergence time was similar between the parents, there was significant transgressive segregation in the population. This was the result of segregation for the previously characterized Ppd-D1a and Ppd-B1 photoperiod responsive alleles. QTL of smaller effect were also detected on chromosomes 1A, 4A, 4B, 5A, 5B, 7A and 7B. A novel QTL for flag leaf glaucousness of large, repeatable effect was detected in six field experiments, on chromosome 3A (QW.aww-3A) and accounted for up to 52 percent of genetic variance for this trait. QW.aww-3A was validated under glasshouse conditions in a recombinant inbred line population from the same cross. The genetic basis of time to ear emergence in this population will aid breeders' understanding of phenological adaptation to the local environment. Novel loci identified for flag leaf glaucousness and the wide phenotypic variation within the DH population offers considerable scope to investigate the impact and value of this trait for bread wheat production in southern Australia.Dion Bennett, Ali Izanloo, James Edwards, Haydn Kuchel, Ken Chalmers, Mark Tester, Matthew Reynolds, Thorsten Schnurbusch, Peter Langridg

Diets and enteral supplements for improving outcomes in chronic kidney disease

Protein-energy wasting (PEW), which is manifested by low serum levels of albumin or prealbumin, sarcopenia and weight loss, is one of the strongest predictors of mortality in patients with chronic kidney disease (CKD). Although PEW might be engendered by non-nutritional conditions, such as inflammation or other comorbidities, the question of causality does not refute the effectiveness of dietary interventions and nutritional support in improving outcomes in patients with CKD. The literature indicates that PEW can be mitigated or corrected with an appropriate diet and enteral nutritional support that targets dietary protein intake. In-center meals or oral supplements provided during dialysis therapy are feasible and inexpensive interventions that might improve survival and quality of life in patients with CKD. Dietary requirements and enteral nutritional support must also be considered in patients with CKD and diabetes mellitus, in patients undergoing peritoneal dialysis, renal transplant recipients, and in children with CKD. Adjunctive pharmacological therapies, such as appetite stimulants, anabolic hormones, and antioxidative or anti-inflammatory agents, might augment dietary interventions. Intraperitoneal or intradialytic parenteral nutrition should be considered for patients with PEW whenever enteral interventions are not possible or are ineffective. Controlled trials are needed to better assess the effectiveness of in-center meals and oral supplements