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

Rahul Tyagi,Fidelis Cho-Ngwa,Matthew Mahoney,Christina A Bulman,Case W Mcnamara,Chelsea Fischer,Nancy Tricoche,Shabnam Jawahar,Judy Sakanari,Chris Marcellino,Sara Lustigman,Michelle R Arkin,James W Janetka,James H Mckerrow,Makedonka Mitreva

doi:10.3390/pathogens10010071

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.

Highlights

River blindness and lymphatic filariasis (LF) are two major neglected tropical diseases (NTD) caused by parasitic nematodes that, together, affect millions of people worldwide in mostly poor, developing countries [1]
20 million people are infected with Onchocerca volvulus; 14.6 million of the infected people have skin disease, 1.2 million people are visually impaired, and 270,000 are blind by river blindness, a chronic disease caused by the first larval stage, microfilariae
A library of 2121 drugs approved for clinical use was screened in a phenotypic assay against adult female B. pahangi at 10 μM (Table S1) using the WormAssay software (University of California San Francisco, San Francisco, CA, USA) and dark-field plate imaging system [41]

Summary

Introduction

River blindness (onchocerciasis) and lymphatic filariasis (LF) are two major neglected tropical diseases (NTD) caused by parasitic nematodes that, together, affect millions of people worldwide in mostly poor, developing countries [1]. International control programs attempt to interrupt transmission of infection with annual or biannual MDA using microfilaricidal drugs (ivermectin since 1989 and more recently moxidectin [8] for onchocerciasis; albendazole and ivermectin or diethylcarbamazine for LF) that kill mf over the lifetime of the adult worms (10–14 years for O. volvulus, 6–8 years for Wuchereria and Brugia spp.) [2,3,4,9,10,11,12,13,14,15,16,17]. These drugs target different critical processes in the mf or make them more susceptible to immune system, e.g., targeting microtubule polymerization (albendazole), glutamate-gated chloride channels and other transporters (ivermectin and moxidectin), and sensitizing microfilariae to phagocytosis by host immune cells (diethylcarbamazine)

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Results

Conclusion