期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 4, 页码 1414-1419出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1816585116
关键词
onchocerciasis; lymphatic filariasis; anti-Wolbachia; drug discovery; macrofilaricide
资金
- Bill & Melinda Gates Foundation [OPP1054324, A.WOL II, A.WOL III]
- Global Health Innovative Technology (GHIT) Fund [GHIT-RFP-2013-002]
- Bill and Melinda Gates Foundation [OPP1054324] Funding Source: Bill and Melinda Gates Foundation
- MRC [MR/R025401/1, MC_PC_16052, MC_PC_17167] Funding Source: UKRI
Onchocerciasis and lymphatic filariasis are two neglected tropical diseases that together affect similar to 157 million people and inflict severe disability. Both diseases are caused by parasitic filarial nematodes with elimination efforts constrained by the lack of a safe drug that can kill the adult filaria (macrofilaricide). Previous proof-of-concept human trials have demonstrated that depleting >90% of the essential nematode endosymbiont bacterium, Wolbachia, using antibiotics, can lead to permanent sterilization of adult female parasites and a safe macrofilaricidal outcome. AWZ1066S is a highly specific anti-Wolbachia candidate selected through a lead optimization program focused on balancing efficacy, safety and drug metabolism/pharmacokinetic (DMPK) features of a thienopyrimidine/quinazoline scaffold derived from phenotypic screening. AWZ1066S shows superior efficacy to existing anti-Wolbachia therapies in validated preclinical models of infection and has DMPK characteristics that are compatible with a short therapeutic regimen of 7 days or less. This candidate molecule is well-positioned for onward development and has the potential to make a significant impact on communities affected by filariasis.
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