Discovery of novel, orally bioavailable, antileishmanial compounds using phenotypic screening
| Autor: | Yizhe Chen, W. Armand Guiguemde, Diana Ortiz, Fangyi Zhu, Kayla Stalheim, Anang A. Shelat, Michele Connelly, Lei Yang, David C. Smithson, Jaeki Min, Alex G. Johnson, Angela K. Carrillo, Carolyn Elya, R. Kiplin Guy, Scott M. Landfear, Jared T. Hammill |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Life Cycles Chemistry Pharmaceutical Leishmania mexicana Drug Evaluation Preclinical Administration Oral Drug resistance Protozoology Pharmacology Mice White Blood Cells Animal Cells Zoonoses Drug Discovery Medicine and Health Sciences Leishmaniasis Mice Inbred BALB C Drug discovery lcsh:Public aspects of medicine Animal Models 3. Good health Phenotype Infectious Diseases Experimental Organism Systems Female Protozoan Life Cycles Cellular Types Research Article Amastigotes Neglected Tropical Diseases medicine.drug lcsh:Arctic medicine. Tropical medicine lcsh:RC955-962 Immune Cells Phenotypic screening Immunology 030106 microbiology Antiprotozoal Agents Leishmaniasis Cutaneous Mouse Models Library Screening Biology Research and Analysis Methods Microbiology Cell Line 03 medical and health sciences Model Organisms Cutaneous leishmaniasis In vivo Parasitic Diseases medicine Animals Humans Pharmacokinetics Molecular Biology Techniques Amastigote Molecular Biology Molecular Biology Assays and Analysis Techniques Miltefosine Blood Cells Protozoan Infections Macrophages Promastigotes Public Health Environmental and Occupational Health Biology and Life Sciences lcsh:RA1-1270 Cell Biology Tropical Diseases medicine.disease biology.organism_classification 030104 developmental biology Developmental Biology |
| Zdroj: | PLoS Neglected Tropical Diseases, Vol 11, Iss 12, p e0006157 (2017) PLoS Neglected Tropical Diseases |
| ISSN: | 1935-2735 1935-2727 |
| Popis: | Leishmaniasis is a parasitic infection that afflicts approximately 12 million people worldwide. There are several limitations to the approved drug therapies for leishmaniasis, including moderate to severe toxicity, growing drug resistance, and the need for extended dosing. Moreover, miltefosine is currently the only orally available drug therapy for this infection. We addressed the pressing need for new therapies by pursuing a two-step phenotypic screen to discover novel, potent, and orally bioavailable antileishmanials. First, we conducted a high-throughput screen (HTS) of roughly 600,000 small molecules for growth inhibition against the promastigote form of the parasite life cycle using the nucleic acid binding dye SYBR Green I. This screen identified approximately 2,700 compounds that inhibited growth by over 65% at a single point concentration of 10 μM. We next used this 2700 compound focused library to identify compounds that were highly potent against the disease-causing intra-macrophage amastigote form and exhibited limited toxicity toward the host macrophages. This two-step screening strategy uncovered nine unique chemical scaffolds within our collection, including two previously described antileishmanials. We further profiled two of the novel compounds for in vitro absorption, distribution, metabolism, excretion, and in vivo pharmacokinetics. Both compounds proved orally bioavailable, affording plasma exposures above the half-maximal effective concentration (EC50) concentration for at least 12 hours. Both compounds were efficacious when administered orally in a murine model of cutaneous leishmaniasis. One of the two compounds exerted potent activity against trypanosomes, which are kinetoplastid parasites related to Leishmania species. Therefore, this compound could help control multiple parasitic diseases. The promising pharmacokinetic profile and significant in vivo efficacy observed from our HTS hits highlight the utility of our two-step phenotypic screening strategy and strongly suggest that medicinal chemistry optimization of these newly identified scaffolds will lead to promising candidates for an orally available anti-parasitic drug. Author summary Leishmaniasis, caused by the protozoa of the Leishmania species, represents a spectrum of diseases that afflicts roughly 12 million individuals worldwide. Current drug therapies for this parasitic disease are suboptimal because they are toxic, expensive, difficult to administer, and subject to drug resistance. In order to identify new and improved drug candidates, we screened a large library of small molecules for compounds that inhibit parasitic growth inside mammalian host macrophages, and have low toxicity toward the macrophages. We discovered two compounds that significantly impaired disease progression when administered orally in an animal model of cutaneous leishmaniasis. The promising pharmacokinetic and in vivo efficacy profile of the compounds make them attractive starting points for pharmaceutical development. |
| Databáze: | OpenAIRE |
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