An Integrated Approach to Identify New Anti-Filarial Leads to Treat River Blindness, a Neglected Tropical Disease
| Autor: | Nancy Tricoche, Shabnam Jawahar, Michelle R. Arkin, Judy A. Sakanari, Matthew Mahoney, Makedonka Mitreva, Christopher Marcellino, Case W. McNamara, Rahul Tyagi, Sara Lustigman, Christina A. Bulman, James H. McKerrow, Chelsea Fischer, Fidelis Cho-Ngwa, James W. Janetka |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Microbiology (medical) Brugia pahangi target class repurposing Phenotypic screening Immunology 030231 tropical medicine lcsh:Medicine Article 03 medical and health sciences 0302 clinical medicine whole worm assay parasitic diseases medicine Immunology and Allergy macrofilaricides Onchocerca Adverse effect Molecular Biology filarial nematodes anthelmintics General Immunology and Microbiology biology Blindness Transmission (medicine) lcsh:R Tropical disease in vitro Integrated approach biology.organism_classification medicine.disease Vector-Borne Diseases Good Health and Well Being 030104 developmental biology Infectious Diseases 5.1 Pharmaceuticals Medical Microbiology parasitic nematodes Development of treatments and therapeutic interventions Infection Biotechnology |
| Zdroj: | Pathogens, Vol 10, Iss 71, p 71 (2021) Pathogens (Basel, Switzerland), vol 10, iss 1 Pathogens Volume 10 Issue 1 |
| ISSN: | 2076-0817 |
| Popis: | Filarial worms cause multiple debilitating diseases in millions of people worldwide, including river blindness. Currently available drugs reduce transmission by killing larvae (microfilariae), but there are no effective cures targeting the adult parasites (macrofilaricides) which survive and reproduce in the host for very long periods. To identify effective macrofilaricides, we carried out phenotypic screening of a library of 2121 approved drugs for clinical use against adult Brugia pahangi and prioritized the hits for further studies by integrating those results with a computational prioritization of drugs and associated targets. This resulted in the identification of 18 hits with anti-macrofilaricidal activity, of which two classes, azoles and aspartic protease inhibitors, were further expanded upon. Follow up screening against Onchocerca spp. (adult Onchocerca ochengi and pre-adult O. volvulus) confirmed activity for 13 drugs (the majority having IC50 < 10 &mu M), and a counter screen of a subset against L. loa microfilariae showed the potential to identify selective drugs that prevent adverse events when co-infected individuals are treated. Stage specific activity was also observed. Many of these drugs are amenable to structural optimization, and also have known canonical targets, making them promising candidates for further optimization that can lead to identifying and characterizing novel anti-macrofilarial drugs. |
| Databáze: | OpenAIRE |
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