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      Route map for the discovery and pre-clinical development of new drugs and treatments for cutaneous leishmaniasis

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          Abstract

          Although there have been significant advances in the treatment of visceral leishmaniasis (VL) and several novel compounds are currently in pre-clinical and clinical development for this manifestation of leishmaniasis, there have been limited advances in drug research and development (R & D) for cutaneous l eishmaniasis (CL). Here we review the need for new treatments for CL, describe in vitro and in vivo assays, models and approaches taken over the past decade to establish a pathway for the discovery, and pre-clinical development of new drugs for CL. These recent advances include novel mouse models of infection using bioluminescent Leishmania, the introduction of PK/PD approaches to skin infection, and defined pre-clinical candidate profiles.

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          Bright and stable near infra-red fluorescent protein for in vivo imaging

          The ability of non-invasive monitoring of deep-tissue developmental, metabolic, and pathogenic processes will advance modern biotechnology. Imaging of live mammals using fluorescent probes is more feasible within a “near-infrared optical window” (NIRW) 1 . Here we report a phytochrome-based near infra-red fluorescent protein (iRFP) with the excitation/emission maxima at 690/713 nm. Bright fluorescence in a living mouse proved iRFP to be a superior probe for non-invasive imaging of internal mammalian tissues. Its high intracellular stability, low cytotoxicity, and lack of the requirement to add external biliverdin-chromophore makes iRFP as easy to use as conventional GFP-like proteins. Compared to earlier phytochrome-derived fluorescent probes, the iRFP protein has better in vitro characteristics and performs well in cells and in vivo, having greater effective brightness and photostability. Compared to the far-red GFP-like proteins, iRFP has substantially higher signal to background ratio in a mouse model owing to its infra-red shifted spectra.
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            Screening out irrelevant cell-based models of disease.

            The common and persistent failures to translate promising preclinical drug candidates into clinical success highlight the limited effectiveness of disease models currently used in drug discovery. An apparent reluctance to explore and adopt alternative cell- and tissue-based model systems, coupled with a detachment from clinical practice during assay validation, contributes to ineffective translational research. To help address these issues and stimulate debate, here we propose a set of principles to facilitate the definition and development of disease-relevant assays, and we discuss new opportunities for exploiting the latest advances in cell-based assay technologies in drug discovery, including induced pluripotent stem cells, three-dimensional (3D) co-culture and organ-on-a-chip systems, complemented by advances in single-cell imaging and gene editing technologies. Funding to support precompetitive, multidisciplinary collaborations to develop novel preclinical models and cell-based screening technologies could have a key role in improving their clinical relevance, and ultimately increase clinical success rates.
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              Leishmania development in sand flies: parasite-vector interactions overview

              Leishmaniases are vector-borne parasitic diseases with 0.9 – 1.4 million new human cases each year worldwide. In the vectorial part of the life-cycle, Leishmania development is confined to the digestive tract. During the first few days after blood feeding, natural barriers to Leishmania development include secreted proteolytic enzymes, the peritrophic matrix surrounding the ingested blood meal and sand fly immune reactions. As the blood digestion proceeds, parasites need to bind to the midgut epithelium to avoid being excreted with the blood remnant. This binding is strictly stage-dependent as it is a property of nectomonad and leptomonad forms only. While the attachment in specific vectors (P. papatasi, P. duboscqi and P. sergenti) involves lipophosphoglycan (LPG), this Leishmania molecule is not required for parasite attachment in other sand fly species experimentally permissive for various Leishmania. During late-stage infections, large numbers of parasites accumulate in the anterior midgut and produce filamentous proteophosphoglycan creating a gel-like plug physically obstructing the gut. The parasites attached to the stomodeal valve cause damage to the chitin lining and epithelial cells of the valve, interfering with its function and facilitating reflux of parasites from the midgut. Transformation to metacyclic stages highly infective for the vertebrate host is the other prerequisite for effective transmission. Here, we review the current state of knowledge of molecular interactions occurring in all these distinct phases of parasite colonization of the sand fly gut, highlighting recent discoveries in the field.
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                Author and article information

                Contributors
                Journal
                Int J Parasitol Drugs Drug Resist
                Int J Parasitol Drugs Drug Resist
                International Journal for Parasitology: Drugs and Drug Resistance
                Elsevier
                2211-3207
                20 June 2019
                December 2019
                20 June 2019
                : 11
                : 106-117
                Affiliations
                [a ]Walter Reed Army Institute for Research, Silver Spring, USA
                [b ]London School of Hygiene and Tropical Medicine, London, UK
                [c ]Drugs for Neglected Diseases Initiative (DNDi), Geneva, Switzerland
                [d ]Department of Immunotherapy and Leishmania Vaccine Research, Institute Pasteur Institute, Tehran, Iran
                [e ]Department of Parasitology, Biomedical Sciences Institute, University of Sao Paulo, Sao Paulo, Brazil
                [f ]Department of Biomedical Science, Universidad de Leon, Leon, Spain
                [g ]INTS, Unite Biologie InteÂgreÂe du Globule Rouge, Laboratoire d'Excellence GR-Ex, Paris, France
                [h ]York Biomedical Research Institute, Department of Biology, University of York, York, UK
                Author notes
                []Corresponding author. Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK. simon.croft@ 123456lshtm.ac.uk
                [1]

                Joint first authors.

                Article
                S2211-3207(19)30078-8
                10.1016/j.ijpddr.2019.06.003
                6904839
                31320296
                feba222b-9b79-443d-9aef-de3ba973baec
                © 2019 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 22 May 2019
                : 16 June 2019
                : 17 June 2019
                Categories
                Includes articles from the special issue “Novel therapies for cutaneous leishmaniasis”, pp. 106 - 179

                cutaneous leishmaniasis,drug discovery,drug development,in vitro assays,in vivo models,pharmacokinetics,formulations,immunomodulatory drugs

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