SC83288 is a clinical development candidate for the treatment of severe malaria

Severe malaria is a life-threatening complication of an infection with the protozoan parasite Plasmodium falciparum, which requires immediate treatment. Safety and efficacy concerns with currently used drugs accentuate the need for new chemotherapeutic options against severe malaria. Here we describe a medicinal chemistry program starting from amicarbalide that led to two compounds with optimized pharmacological and antiparasitic properties. SC81458 and the clinical development candidate, SC83288, are fast-acting compounds that can cure a P. falciparum infection in a humanized NOD/SCID mouse model system. Detailed preclinical pharmacokinetic and toxicological studies reveal no observable drawbacks. Ultra-deep sequencing of resistant parasites identifies the sarco/endoplasmic reticulum Ca(2+) transporting PfATP6 as a putative determinant of resistance to SC81458 and SC83288. Features, such as fast parasite killing, good safety margin, a potentially novel mode of action and a distinct chemotype support the clinical development of SC83288, as an intravenous application for the treatment of severe malaria

Towards an In Vitro Model of Plasmodium Hypnozoites Suitable for Drug Discovery

Contains fulltext : 96475.pdf (publisher's version ) (Open Access)BACKGROUND: Amongst the Plasmodium species in humans, only P. vivax and P. ovale produce latent hepatic stages called hypnozoites, which are responsible for malaria episodes long after a mosquito bite. Relapses contribute to increased morbidity, and complicate malaria elimination programs. A single drug effective against hypnozoites, primaquine, is available, but its deployment is curtailed by its haemolytic potential in glucose-6-phosphate dehydrogenase deficient persons. Novel compounds are thus urgently needed to replace primaquine. Discovery of compounds active against hypnozoites is restricted to the in vivo P. cynomolgi-rhesus monkey model. Slow growing hepatic parasites reminiscent of hypnozoites had been noted in cultured P. vivax-infected hepatoma cells, but similar forms are also observed in vitro by other species including P. falciparum that do not produce hypnozoites. METHODOLOGY: P. falciparum or P. cynomolgi sporozoites were used to infect human or Macaca fascicularis primary hepatocytes, respectively. The susceptibility of the slow and normally growing hepatic forms obtained in vitro to three antimalarial drugs, one active against hepatic forms including hypnozoites and two only against the growing forms, was measured. RESULTS: The non-dividing slow growing P. cynomolgi hepatic forms, observed in vitro in primary hepatocytes from the natural host Macaca fascicularis, can be distinguished from similar forms seen in P. falciparum-infected human primary hepatocytes by the differential action of selected anti-malarial drugs. Whereas atovaquone and pyrimethamine are active on all the dividing hepatic forms observed, the P. cynomolgi slow growing forms are highly resistant to treatment by these drugs, but remain susceptible to primaquine. CONCLUSION: Resistance of the non-dividing P. cynomolgi forms to atovaquone and pyrimethamine, which do not prevent relapses, strongly suggests that these slow growing forms are hypnozoites. This represents a first step towards the development of a practical medium-throughput in vitro screening assay for novel hypnozoiticidal drugs

Modern and fossil non-pollen palynomorphs from the Basque mountains (western Pyrenees, France): the use of coprophilous fungi to reconstruct pastoral activity

International audienceThis paper presents results from a modern dataset of non-pollen palynomorphs and its application to aca. 2,000 year peat record from the same area in the western Pyrenees (Basque Country, France). The modern dataset is composed of 35 surface samples (moss polsters) from a mountainous pasture-woodland landscape. Airborne fungal spores (ascospores and conidia), found dominant in the dataset, are linked to the degree of landscape openness and grazing pressure. The complete spectrum of 13 selected spore-types of dung-related Ascomycetes is positively linked with grazing pressure. However, different dung affinities between the spore-types have been identified. These are types clearly related to high grazing pressure and types with no or unclear dung indicative value. The modern dataset is used to aid interpretation of the local fossil pollen record as an independent 'proxy' to assess past pastoral dynamics. This study confirms the utility of modern nonpollen palynomorphs from terrestrial ecosystems in the reconstruction of historical local pastoral activities but also shows their limitation. It may be necessary to extend such study to wetland ecosystems and to investigate the spatial dimension of some fungal spores

Pollen productivity estimates of key European plant taxa for quantitative reconstruction of past vegetation: a review

International audienceInformation on the spatial distribution of past vegetation on local, regional and global scales is increasingly used within climate modelling, nature conservancy and archaeology. It is possible to obtain such information from fossil pollen records in lakes and bogs using the landscape reconstruction algorithm (LRA) and its two models, REVEALS and LOVE. These models assume that reliable pollen productivity estimates (PPEs) are available for the plant taxa involved in the quantitative reconstruc -tions of past vegetation, and that PPEs are constant through time. This paper presents and discusses the PPEs for 15 tree and 18 herb taxa obtained in nine study areas of Europe. Observed differences in PPEs between regions may be explained by methodological issues and environmental variables, of which climate and related factors such as reproduction strategies and growth forms appear to be the most important. An evaluation of the PPEs at hand so far suggests that they can be used in modelling applications and quantitative reconstructions of pastvegetation, provided that consideration of past environmental variability within the region is used to inform selection of PPEs, and bearing in mind that PPEs might have changed through time as a response to climate change. Application of a range of possible PPEs will allow a better evaluation of the results

Erratum: SC83288 is a clinical development candidate for the treatment of severe malaria

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Multidisciplinary approach to reconstructing local pastoral activities: an example from the Pyrenean Mountains (Pays Basque)

International audienceIn this study archaeology, history and palaeoecology (modern and fossil data sets of pollen and nonpollen palynomorphs) were used to reconstruct small-scale pastoral activities in the Pyrenees Mountains during the last two millennia. Modern pollen assemblages from the major vegetation units (both natural andanthropogenic) are studied on one restricted watershed area. A correlative model (RDA) of 61 modern pollen spectra and 35 external variables distinguishes two groups of taxa, providing information on the nature and spatial extent of human impact on the landscape. The first pool indicates local pastoral activities, and the second one implies regional input from outside the studied watershed, and is not characteristic of a specific land use. These pools are described as 'Local Pastoral Pollen Indicators' (LPPI) for this particular mountain region on crystalline bedrock and 'Regional Human Activities Pollen Indicators' (RHAPI). The modern data set is used to aid interpretation of the local pollen sequence of Sourzay that covers the last 2000 calendar years BP, using RDA reconstructions, and best modern analogues as a means of comparing modern and fossil spectra. The study also demonstrates agreement between the independent interpretations of two fossil proxies, LPPI and coprophilous fungi

Holocene changes in vegetation composition in northern Europe: why quantitative pollen-based vegetation reconstructions matter

International audienceWe present pollen-based reconstructions of the spatio-temporal dynamics of northern European regional vegetation abundance through the Holocene. We apply the Regional Estimates of VEgetation Abundance from Large Sites (REVEALS) model using fossil pollen records from eighteen sites within five modern biomes in the region. The eighteen sites are classified into four time-trajectory types on the basis of principal components analysis of both the REVEALS-based vegetation estimates (RVs) and the pollen percentage (PPs). The four trajectory types are more clearly separated for RVs than PPs. Further, the timing of major Holocene shifts, rates of compositional change, and diversity indices (turnover and evenness) differ between RVs and PPs. The differences are due to the reduction by REVEALS of biases in fossil pollen assemblages caused by different basin size, and inter-taxonomic differences in pollen productivity and dispersal properties. For example, in comparison to the PPs, the RVs show an earlier increase in Corylus and Ulmus in the early-Holocene and a more pronounced increase in grassland and deforested areas since the mid-Holocene. The results suggest that the influence of deforestation and agricultural activities on plant composition and abundance from Neolithic times was stronger than previously inferred from PPs. Relative to PPs, RVs show a more rapid compositional change, a largest decrease in turnover, and less variable evenness in most of northern Europe since 5200 cal yr BP. All these changes are primarily related to the strong impact of human activities on the vegetation. This study demonstrates that RV-based estimates of diversity indices, timing of shifts, and rates of change in reconstructed vegetation provide new insights into the timing and magnitude of major humandisturbance on Holocene regional vegetation, features that are critical in the assessment of humanimpact on vegetation, land-cover, biodiversity, and climate in the past

Europe's lost forests: a pollen-based synthesis for the last 11,000 years

8000 years ago, prior to Neolithic agriculture, Europe was mostly a wooded continent. Since then, its forest cover has been progressively fragmented, so that today it covers less than half of Europe’s land area, in many cases having been cleared to make way for fields and pasture-land. Establishing the origin of Europe’s current, more open land-cover mosaic requires a long-term perspective, for which pollen analysis offers a key tool. In this study we utilise and compare three numerical approaches to transforming pollen data into past forest cover, drawing on >1000 14C-dated site records. All reconstructions highlight the different histories of the mixed temperate and the northern boreal forests, with the former declining progressively since ~6000 years ago, linked to forest clearance for agriculture in later prehistory (especially in northwest Europe) and early historic times (e.g. in north central Europe). In contrast, extensive human impact on the needle-leaf forests of northern Europe only becomes detectable in the last two millennia and has left a larger area of forest in place. Forest loss has been a dominant feature of Europe’s landscape ecology in the second half of the current interglacial, with consequences for carbon cycling, ecosystem functioning and biodiversity