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Targeting the Genus Leishmania with Small Molecules

用小分子靶向利什曼原虫属

基本信息

批准号：
10579191
负责人：
Lauren Elaine Brown
金额：
$ 75.15万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-24 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10579191
关键词：
Academia Address Adhesives Adverse effects Affect Affinity American Amphotericin B Antimony Antineoplastic Agents Antiparasitic Agents Behavior Biological Assay Biology Bone Marrow Boston Cells Chemicals Clinical Collaborations Country Cutaneous Cutaneous Leishmaniasis Development Disease Dose Drug Delivery Systems Drug Kinetics Drug Targeting Exhibits Experimental Models Formulation Genetic Goals Grant Hospitalization Immune system In Vitro Infection Knock-out Knowledge Laboratory Finding Lead Leishmania Leishmania donovani Leishmaniasis Lesion Liver Macrophage Medical Methodology Military Personnel Miltefosine Modeling Molecular Target Mucocutaneous leishmaniasis Mucous Membrane Mutation Oklahoma Oral Organ Organism Outcome Parasite resistance Parasites Parasitic Diseases Parasitology Penetration Persons Pharmaceutical Preparations Phenotype Phlebotominae Population Populations at Risk Predisposition Reagent Regional Disease Reporting Research Resistance Route Sand Flies Series Skin Spleen Structure-Activity Relationship Techniques Teratogens Testing Texas Therapeutic Topical application Toxic effect Universities Validation Visceral Visceral Leishmaniasis Work Yeasts alternative treatment analog biocompatible polymer chemotherapy cytotoxic deep sequencing design drug candidate drug discovery ear infection genome analysis human disease improved in vivo innovation lead series liposomal formulation member meter monocyte nanomolar neglect novel therapeutics pharmacologic pre-clinical programs screening side effect skin ulcer small molecule transmission process vector

项目摘要

PROJECT SUMMARY AND ABSTRACT Targeting the Genus Leishmania with Small Molecules Leishmaniasis is a neglected disease caused by protozoan parasites from the genus Leishmania sp. It is transmitted by the sandfly vector and manifests in different clinical forms including skin ulcers, mucosa destruction, damage to visceral organs such as the liver and spleen, and bone marrow damage. The clinical outcome is determined primarily by the species of the parasite and the immune system of the host. There are 98 countries affected by leishmaniasis with more than 2 million people currently infected and 350 million people at risk. The spread of leishmaniasis is of particular concern to US citizens in southern states such as Texas and Oklahoma, where cases have recently been reported, as well as to US military troops stationed abroad in geopolitically unstable regions where the disease tends to thrive. Chemotherapy options for leishmaniasis are limited. Antimonials have been the first line drug for decades in most endemic countries, despite antimony’s notorious adverse effects, hospitalization requirements and increasing cases of antimony-resistant parasites. Amphotericin B, the main alternative treatment, also causes significant harmful side effects. Liposomal formulations are better tolerated, but are prohibitively expensive for most affected populations. Miltefosine, an anti-cancer drug, was recently repurposed to treat leishmaniasis and is the only oral treatment available and approved for use in the US. Miltefosine also has toxicity limitations, teratogenicity and lack of efficacy against certain Leishmania species. The development of new chemotherapies to treat the different clinical forms of leishmaniasis is in urgent demand, and is clearly an unmet medical need. To address this unmet medical need, Scott Schaus and Lauren Brown from Boston University (BU) will lead a collaborative project with Jair Lage Siqueira-Neto at the UC San Diego Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Camila Indiani de Oliveira at FIOCRUZ and Mark Grinstaff at BU to characterize the activity of antileishmanial small molecules and develop them as systemic and topical therapeutics. Preliminary work by the team has led to the identification of a chemotype with nanomolar in vitro efficacy against both visceral- and cutaneous-causative species of the parasite, a suitable pharmacokinetic profile for in vivo studies, and demonstrated in vivo efficacy in a cutaneous leishmaniasis infection model. This grant outlines a proposal to further develop the chemotype and address specific challenges in antileishmanial drug discovery, including drug target identification, options for dosing and administration, and most importantly the applicability of the chemotype to treat multiple manifestations of the disease, including those that are most relevant and endemic to the American continents. Our end goal is to develop at least one pre- clinical candidate for the treatment of either visceral or cutaneous leishmaniasis.

项目总结与摘要