AWZ1066S, a highly specific anti- drug candidate for a short-course treatment of filariasis.

W. David Hong; Farid Benayoud; Gemma L. Nixon; Louise Ford; Kelly Johnston; Rachel Clare; Andrew Cassidy; Darren A.N. Cook; Amy Siu; Motohiro Shiotani; Peter J.H. Webborn; Stefan Kavanagh; Ghaith Aljayyoussi; Emma Murphy; Andrew Steven; John Archer; Dominique Struever; Stefan J. Frohberger; Alexandra Ehrens; Marc P. Hübner; Achim Hoerauf; Adam Roberts; Alasdair Hubbard; Edward W. Tate; Remigiusz A. Serwa; Suet C. Leung; Li Qie; Neil G. Berry; Fabian Gusovsky; Janet Hemingway; Joseph Turner; Mark Taylor; Steve Ward; Paul M. O’Neill

doi:10.1073/pnas.1816585116

AWZ1066S, a highly specific anti- drug candidate for a short-course treatment of filariasis.

W. David Hong, Farid Benayoud, Gemma L. Nixon, Louise Ford, Kelly Johnston, Rachel Clare, Andrew Cassidy, Darren A.N. Cook, Amy Siu, Motohiro Shiotani, Peter J.H. Webborn, Stefan Kavanagh, Ghaith Aljayyoussi, Emma Murphy, Andrew Steven, John Archer, Dominique Struever, Stefan J. Frohberger, Alexandra Ehrens, Marc P. HübnerAchim Hoerauf, Adam Roberts, Alasdair Hubbard, Edward W. Tate, Remigiusz A. Serwa, Suet C. Leung, Li Qie, Neil G. Berry, Fabian Gusovsky, Janet Hemingway, Joseph Turner, Mark Taylor, Steve Ward, Paul M. O’Neill

Research output: Contribution to journal › Article › peer-review

57 Citations (Scopus)

Abstract

Onchocerciasis and lymphatic filariasis are two neglected tropical diseases that together affect ∼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, , using antibiotics, can lead to permanent sterilization of adult female parasites and a safe macrofilaricidal outcome. AWZ1066S is a highly specific anti- 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- 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.

Original language	English
Pages (from-to)	1414-1419
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	116
Issue number	4
Early online date	7 Jan 2019
DOIs	https://doi.org/10.1073/pnas.1816585116
Publication status	Published - 22 Jan 2019

Keywords

Anti-Wolbachia
Drug discovery
Lymphatic filariasis
Macrofilaricide
Onchocerciasis

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1073/pnas.1816585116Licence: CC BY-NC-ND

PNAS AWZ1066SFinal published version, 1.23 MBLicence: CC BY-NC-ND

Cite this

David Hong, W., Benayoud, F., Nixon, G. L., Ford, L., Johnston, K., Clare, R., Cassidy, A., Cook, D. A. N., Siu, A., Shiotani, M., Webborn, P. J. H., Kavanagh, S., Aljayyoussi, G., Murphy, E., Steven, A., Archer, J., Struever, D., Frohberger, S. J., Ehrens, A., ... O’Neill, P. M. (2019). AWZ1066S, a highly specific anti- drug candidate for a short-course treatment of filariasis. Proceedings of the National Academy of Sciences of the United States of America, 116(4), 1414-1419. https://doi.org/10.1073/pnas.1816585116

@article{009b152ba1db4f8f9ee81d658ac60ade,

title = "AWZ1066S, a highly specific anti- drug candidate for a short-course treatment of filariasis.",

abstract = "Onchocerciasis and lymphatic filariasis are two neglected tropical diseases that together affect ∼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, , using antibiotics, can lead to permanent sterilization of adult female parasites and a safe macrofilaricidal outcome. AWZ1066S is a highly specific anti- 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- 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.",

keywords = "Anti-Wolbachia, Drug discovery, Lymphatic filariasis, Macrofilaricide, Onchocerciasis",

author = "\{David Hong\}, W. and Farid Benayoud and Nixon, \{Gemma L.\} and Louise Ford and Kelly Johnston and Rachel Clare and Andrew Cassidy and Cook, \{Darren A.N.\} and Amy Siu and Motohiro Shiotani and Webborn, \{Peter J.H.\} and Stefan Kavanagh and Ghaith Aljayyoussi and Emma Murphy and Andrew Steven and John Archer and Dominique Struever and Frohberger, \{Stefan J.\} and Alexandra Ehrens and H{\"u}bner, \{Marc P.\} and Achim Hoerauf and Adam Roberts and Alasdair Hubbard and Tate, \{Edward W.\} and Serwa, \{Remigiusz A.\} and Leung, \{Suet C.\} and Li Qie and Berry, \{Neil G.\} and Fabian Gusovsky and Janet Hemingway and Joseph Turner and Mark Taylor and Steve Ward and O{\textquoteright}Neill, \{Paul M.\}",

year = "2019",

month = jan,

day = "22",

doi = "10.1073/pnas.1816585116",

language = "English",

volume = "116",

pages = "1414--1419",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "4",

}

David Hong, W, Benayoud, F, Nixon, GL, Ford, L , Johnston, K, Clare, R, Cassidy, A, Cook, DAN, Siu, A, Shiotani, M, Webborn, PJH, Kavanagh, S, Aljayyoussi, G, Murphy, E, Steven, A, Archer, J, Struever, D, Frohberger, SJ, Ehrens, A, Hübner, MP, Hoerauf, A, Roberts, A, Hubbard, A, Tate, EW, Serwa, RA, Leung, SC, Qie, L, Berry, NG, Gusovsky, F, Hemingway, J , Turner, J , Taylor, M , Ward, S & O’Neill, PM 2019, 'AWZ1066S, a highly specific anti- drug candidate for a short-course treatment of filariasis.', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 4, pp. 1414-1419. https://doi.org/10.1073/pnas.1816585116

TY - JOUR

T1 - AWZ1066S, a highly specific anti- drug candidate for a short-course treatment of filariasis.

AU - David Hong, W.

AU - Benayoud, Farid

AU - Nixon, Gemma L.

AU - Ford, Louise

AU - Johnston, Kelly

AU - Clare, Rachel

AU - Cassidy, Andrew

AU - Cook, Darren A.N.

AU - Siu, Amy

AU - Shiotani, Motohiro

AU - Webborn, Peter J.H.

AU - Kavanagh, Stefan

AU - Aljayyoussi, Ghaith

AU - Murphy, Emma

AU - Steven, Andrew

AU - Archer, John

AU - Struever, Dominique

AU - Frohberger, Stefan J.

AU - Ehrens, Alexandra

AU - Hübner, Marc P.

AU - Hoerauf, Achim

AU - Roberts, Adam

AU - Hubbard, Alasdair

AU - Tate, Edward W.

AU - Serwa, Remigiusz A.

AU - Leung, Suet C.

AU - Qie, Li

AU - Berry, Neil G.

AU - Gusovsky, Fabian

AU - Hemingway, Janet

AU - Turner, Joseph

AU - Taylor, Mark

AU - Ward, Steve

AU - O’Neill, Paul M.

PY - 2019/1/22

Y1 - 2019/1/22

N2 - Onchocerciasis and lymphatic filariasis are two neglected tropical diseases that together affect ∼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, , using antibiotics, can lead to permanent sterilization of adult female parasites and a safe macrofilaricidal outcome. AWZ1066S is a highly specific anti- 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- 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.

AB - Onchocerciasis and lymphatic filariasis are two neglected tropical diseases that together affect ∼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, , using antibiotics, can lead to permanent sterilization of adult female parasites and a safe macrofilaricidal outcome. AWZ1066S is a highly specific anti- 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- 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.

KW - Anti-Wolbachia

KW - Drug discovery

KW - Lymphatic filariasis

KW - Macrofilaricide

KW - Onchocerciasis

U2 - 10.1073/pnas.1816585116

DO - 10.1073/pnas.1816585116

M3 - Article

SN - 0027-8424

VL - 116

SP - 1414

EP - 1419

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 4

ER -

AWZ1066S, a highly specific anti- drug candidate for a short-course treatment of filariasis.

Abstract

Keywords

UN SDGs

Access to Document

Fingerprint

Cite this