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An Integrated Approach to Identify New Anti-Filarial Leads to Treat River Blindness, a Neglected Tropical Disease

Authors :
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
Source :
Pathogens, Vol 10, Iss 1, p 71 (2021)
Publication Year :
2021
Publisher :
MDPI AG, 2021.

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 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 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.

Details

Language :
English
ISSN :
20760817
Volume :
10
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Pathogens
Publication Type :
Academic Journal
Accession number :
edsdoj.4b9a387fd8184bb3b46400e12541ea35
Document Type :
article
Full Text :
https://doi.org/10.3390/pathogens10010071