An integrated approach to identify new anti-filarial leads to treat river blindness, a neglected tropical disease

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

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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 antimacrofilaricidal 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 μM), 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.

Original languageEnglish
Article number71
Pages (from-to)1-22
Number of pages22
JournalPathogens
Volume10
Issue number1
DOIs
StatePublished - Jan 2021

Keywords

  • Anthelmintics
  • Filarial nematodes
  • In vitro
  • Macrofilaricides
  • Parasitic nematodes
  • Target class repurposing
  • Whole worm assay

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