Pyrvinium Pamoate and Structural Analogs Are Early Macrofilaricide Leads.

Emma L Gunderson,Denis Voronin,Sara Lustigman,Chelsea Fischer,Adam R Renslo,Brenda Beerntsen,Shabnam Jawahar,Glory E Mbah,Ian Vogel,Mona Luo,Nancy Tricoche,Judy A Sakanari,Christina A Bulman,Kee-Chong Lim,Rene B Ayiseh,Christopher Corbo,Fidelis Cho-Ngwa,Faustin P T Manfo,Clifford Bryant

doi:10.3390/ph15020189

Abstract

Onchocerciasis and lymphatic filariasis are neglected tropical diseases caused by infection with filarial worms. Annual or biannual mass drug administration with microfilaricidal drugs that kill the microfilarial stages of the parasites has helped reduce infection rates and thus prevent transmission of both infections. However, success depends on high population coverage that is maintained for the duration of the adult worm’s lifespan. Given that these filarial worms can live up to 14 years in their human hosts, a macrofilaricidal drug would vastly accelerate elimination efforts. Here, we have evaluated the repurposed drug pyrvinium pamoate as well as newly synthesized analogs of pyrvinium for their efficacy against filarial worms in vitro and in vivo. We found that pyrvinium pamoate, tetrahydropyrvinium and one of the analogs were highly potent in inhibiting worms in in vitro whole-worm screening assays, and that all three compounds reduced female worm fecundity and inhibited embryogenesis in the Brugia pahangi-gerbil in vivo model of infection.

Highlights

According to the 2017 Global Burden of Disease Study, over 20 million people worldwide are infected with the filarial worm Onchocerca volvulus, which causes onchocerciasis, and nearly 65 million people are infected with Wuchereria bancrofti, Brugia malayi or B. timori, the filarial worms that cause lymphatic filariasis (LF) [1]
The present study identified two new analogs, tetrahydropyrvinium (THP) and pyrvinium analog 06, as the most promising early macrofilaricidal compounds using in vitro phenotypic screens and the Brugia pahangi-gerbil model of infection
pyrvinium pamoate (PVP), tetrahydropyrvinium (THP), and six other PVP analogs that were modified at the quinoline or pyrrole rings (Figure 1) were initially screened in a B. pahangi adult female motility assay

Summary

Introduction

According to the 2017 Global Burden of Disease Study, over 20 million people worldwide are infected with the filarial worm Onchocerca volvulus, which causes onchocerciasis, and nearly 65 million people are infected with Wuchereria bancrofti, Brugia malayi or B. timori, the filarial worms that cause lymphatic filariasis (LF) [1]. Onchocerciasis, known as river blindness, is a chronic disease caused by the first larval stage, microfilariae (mf), that are released from female worms residing in subcutaneous tissues. The mf migrate throughout the skin, causing severe pruritus, and when they migrate to the eyes, they induce an inflammatory response that eventually leads to impaired vision and blindness. Lymphatic filariasis (elephantiasis) is a chronic disease but the pathology is associated with the Pharmaceuticals 2022, 15, 189. Pharmaceuticals 2022, 15, 189 adult stages that induce inflammation that can permanently damage host lymphatic tissues [2]. Symptoms of this disease include chronic pain associated with severe lymphedema typically in the arms, legs, breasts and genitalia. LF and onchocerciasis cause over 2.7 million years lived with disability (YLDs) to people living in impoverished countries [1]

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