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Discovery of short-course antiwolbachial quinazolines for elimination of filarial worm infections

Authors :
Hanna T. Sjoberg
Mark J. Taylor
Bertrand L. Ndzeshang
William J. Sullivan
Mitchell V. Hull
Franziska Lenz
Wen Xiong
Case W. McNamara
Haelly M. Metuge
Nicolas Pionnier
Kelli Kuhen
Stefan J. Frohberger
Ashley K. Woods
Samuel Wanji
Laura Chappell
Frédéric Landmann
Xin-Jie Chu
Joseph D. Turner
Tayong Dizzle Bita Kwenti
Alain Debec
Achim Hoerauf
Bettina Dubben
Jason Roland
Matt S. Tremblay
Narcisse Victor T. Gandjui
Peter G. Schultz
Arnab K. Chatterjee
Jason Olejniczak
Baiyuan Yang
Patrick W. N. Chounna
Fanny Fri Fombad
Andrew Steven
Roohollah Kazem Shiroodi
Dominique Struever
Malina A. Bakowski
Sean B. Joseph
Renhe Liu
H. Michael Petrassi
Kerstin Mae Gagaring
John Archer
Emma A Murphy
Pamela M. White
Desmond N. Akumtoh
Valerine C. Chunda
Abdel Jelil Njouendou
Marc P. Hübner
Hui Guo
Alexandra Ehrens
Department of Chemistry and Biochemistry, San Diego
San Diego State University (SDSU)
Institut Jacques Monod (IJM (UMR_7592))
Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)
Centre de recherche en Biologie Cellulaire (CRBM)
Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)
University Hospital Bonn
Laboratoire de Tribologie et Dynamique des Systèmes (LTDS)
École Centrale de Lyon (ECL)
Université de Lyon-Université de Lyon-École Nationale des Travaux Publics de l'État (ENTPE)-Ecole Nationale d'Ingénieurs de Saint Etienne-Centre National de la Recherche Scientifique (CNRS)
National Center for Biotechnology Information (NCBI)
University of Manchester [Manchester]
California Institute for Biomedical Research - calibr
Scripps Research Institute
Wuhan National Laboratory for Optoelectronics
Huazhong University of Science and Technology [Wuhan] (HUST)
Sandia National Laboratories [Albuquerque] (SNL)
Sandia National Laboratories - Corporation
Source :
Science Translational Medicine, Science Translational Medicine, American Association for the Advancement of Science, 2019, 11 (491), pp.eaav3523. ⟨10.1126/scitranslmed.aav3523⟩
Publication Year :
2019
Publisher :
HAL CCSD, 2019.

Abstract

Parasitic filarial nematodes cause debilitating infections in people in resource-limited countries. A clinically validated approach to eliminating worms uses a 4- to 6-week course of doxycycline that targetsWolbachia, a bacterial endosymbiont required for worm viability and reproduction. However, the prolonged length of therapy and contraindication in children and pregnant women have slowed adoption of this treatment. Here, we describe discovery and optimization of quinazolines CBR417 and CBR490 that, with a single dose, achieve >99% elimination ofWolbachiain the in vivoLitomosoides sigmodontisfilarial infection model. The efficacious quinazoline series was identified by pairing a primary cell-based high-content imaging screen with an orthogonal ex vivo validation assay to rapidly quantifyWolbachiaelimination inBrugia pahangifilarial ovaries. We screened 300,368 small molecules in the primary assay and identified 288 potent and selective hits. Of 134 primary hits tested, only 23.9% were active in the worm-based validation assay, 8 of which contained a quinazoline heterocycle core. Medicinal chemistry optimization generated quinazolines with excellent pharmacokinetic profiles in mice. Potent antiwolbachial activity was confirmed inL. sigmodontis,Brugia malayi, andOnchocerca ochengiin vivo preclinical models of filarial disease and in vitro selectivity againstLoa loa(a safety concern in endemic areas). The favorable efficacy and in vitro safety profiles of CBR490 and CBR417 further support these as clinical candidates for treatment of filarial infections.

Details

Language :
English
ISSN :
19466234 and 19466242
Database :
OpenAIRE
Journal :
Science Translational Medicine, Science Translational Medicine, American Association for the Advancement of Science, 2019, 11 (491), pp.eaav3523. ⟨10.1126/scitranslmed.aav3523⟩
Accession number :
edsair.doi.dedup.....f5b7dd2acbde369889842c0450e10664
Full Text :
https://doi.org/10.1126/scitranslmed.aav3523⟩