An Integrated Approach to Identify New Anti-Filarial Leads to Treat River Blindness, a Neglected Tropical Disease
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 reprodu...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-01-01
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| Series: | Pathogens |
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| Online Access: | https://www.mdpi.com/2076-0817/10/1/71 |
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| author | Rahul Tyagi Christina A. Bulman Fidelis Cho-Ngwa Chelsea Fischer Chris Marcellino Michelle R. Arkin James H. McKerrow Case W. McNamara Matthew Mahoney Nancy Tricoche Shabnam Jawahar James W. Janetka Sara Lustigman Judy Sakanari Makedonka Mitreva |
| author_facet | Rahul Tyagi Christina A. Bulman Fidelis Cho-Ngwa Chelsea Fischer Chris Marcellino Michelle R. Arkin James H. McKerrow Case W. McNamara Matthew Mahoney Nancy Tricoche Shabnam Jawahar James W. Janetka Sara Lustigman Judy Sakanari Makedonka Mitreva |
| author_sort | Rahul Tyagi |
| collection | DOAJ |
| description | 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 <i>Brugia pahangi</i> 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 <i>Onchocerca</i> spp. (adult <i>Onchocerca ochengi</i> and pre-adult <i>O. volvulus</i>) confirmed activity for 13 drugs (the majority having IC<sub>50</sub> < 10 μM), and a counter screen of a subset against <i>L. loa</i> 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. |
| first_indexed | 2024-03-09T04:44:48Z |
| format | Article |
| id | doaj.art-4b9a387fd8184bb3b46400e12541ea35 |
| institution | Directory Open Access Journal |
| issn | 2076-0817 |
| language | English |
| last_indexed | 2024-03-09T04:44:48Z |
| publishDate | 2021-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pathogens |
| spelling | doaj.art-4b9a387fd8184bb3b46400e12541ea352023-12-03T13:16:51ZengMDPI AGPathogens2076-08172021-01-011017110.3390/pathogens10010071An Integrated Approach to Identify New Anti-Filarial Leads to Treat River Blindness, a Neglected Tropical DiseaseRahul Tyagi0Christina A. Bulman1Fidelis Cho-Ngwa2Chelsea Fischer3Chris Marcellino4Michelle R. Arkin5James H. McKerrow6Case W. McNamara7Matthew Mahoney8Nancy Tricoche9Shabnam Jawahar10James W. Janetka11Sara Lustigman12Judy Sakanari13Makedonka Mitreva14Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, 4523 Clayton Ave., St. Louis, MO 63110, USADepartment of Pharmaceutical Chemistry, University of California San Francisco, 1700 4th Street, San Francisco, CA 94158, USAANDI Centre of Excellence for Onchocerciasis Drug Research, Biotechnology Unit, Faculty of Science, University of Buea, Buea CM-00237, CameroonDepartment of Pharmaceutical Chemistry, University of California San Francisco, 1700 4th Street, San Francisco, CA 94158, USADivision of Neurocritical Care and Hospital Neurology, Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USADepartment of Pharmaceutical Chemistry, University of California San Francisco, 1700 4th Street, San Francisco, CA 94158, USASkaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA 92093, USACalibr, a Division of The Scripps Research Institute, 11119 Torrey Pines Road, La Jolla, CA 92037, USADepartment of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USALindsley F. Kimball Research Institute, New York City, NY 10065, USALindsley F. Kimball Research Institute, New York City, NY 10065, USADepartment of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USALindsley F. Kimball Research Institute, New York City, NY 10065, USADepartment of Pharmaceutical Chemistry, University of California San Francisco, 1700 4th Street, San Francisco, CA 94158, USADivision of Infectious Diseases, Department of Medicine, Washington University School of Medicine, 4523 Clayton Ave., St. Louis, MO 63110, USAFilarial 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 <i>Brugia pahangi</i> 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 <i>Onchocerca</i> spp. (adult <i>Onchocerca ochengi</i> and pre-adult <i>O. volvulus</i>) confirmed activity for 13 drugs (the majority having IC<sub>50</sub> < 10 μM), and a counter screen of a subset against <i>L. loa</i> 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.https://www.mdpi.com/2076-0817/10/1/71parasitic nematodesfilarial nematodeswhole worm assayin vitrotarget class repurposinganthelmintics |
| spellingShingle | Rahul Tyagi Christina A. Bulman Fidelis Cho-Ngwa Chelsea Fischer Chris Marcellino Michelle R. Arkin James H. McKerrow Case W. McNamara Matthew Mahoney Nancy Tricoche Shabnam Jawahar James W. Janetka Sara Lustigman Judy Sakanari Makedonka Mitreva An Integrated Approach to Identify New Anti-Filarial Leads to Treat River Blindness, a Neglected Tropical Disease Pathogens parasitic nematodes filarial nematodes whole worm assay in vitro target class repurposing anthelmintics |
| title | An Integrated Approach to Identify New Anti-Filarial Leads to Treat River Blindness, a Neglected Tropical Disease |
| title_full | An Integrated Approach to Identify New Anti-Filarial Leads to Treat River Blindness, a Neglected Tropical Disease |
| title_fullStr | An Integrated Approach to Identify New Anti-Filarial Leads to Treat River Blindness, a Neglected Tropical Disease |
| title_full_unstemmed | An Integrated Approach to Identify New Anti-Filarial Leads to Treat River Blindness, a Neglected Tropical Disease |
| title_short | An Integrated Approach to Identify New Anti-Filarial Leads to Treat River Blindness, a Neglected Tropical Disease |
| title_sort | integrated approach to identify new anti filarial leads to treat river blindness a neglected tropical disease |
| topic | parasitic nematodes filarial nematodes whole worm assay in vitro target class repurposing anthelmintics |
| url | https://www.mdpi.com/2076-0817/10/1/71 |
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