TY - JOUR
T1 - Filarial nematode phenotypic screening cascade to identify compounds with anti-parasitic activity for drug discovery optimization
AU - Hawryluk, Natalie
AU - Zhiru, Li
AU - Carlow, Clotilde
AU - Gokool, Suzanne
AU - Townson, Simon
AU - Kreiss, Tamara
AU - Chojnowski, Agnieszka
AU - Prorok, Monika
AU - Siekierka, John
AU - Ehrens, Alexandra
AU - Koschel, Marianne
AU - Lhermitte-Vallarino, Nathaly
AU - Martin, Coralie
AU - Hoerauf, Achim
AU - Hernandez, Geraldine
AU - Canan, Stacie
AU - Khetani, Vikram
AU - Zeldis, Jerome
AU - Specht, Sabine
AU - Hübner, Marc P.
AU - Scandale, Ivan
N1 - Funding Information:
Part of the work described in this paper was funded by former Celgene, currently Bristol Myers Squibb (BMS) and New England Biolabs . NAH, SC, and VK are former employees of BMS. GH is an employee of BMS. JZ is a former employee of Celgene. ZL and CC are employees of New England Biolabs. Work by SG, ST, AE, MK, N L-V, CM, AH, SS, and MH was funded by the Drugs for Neglected Diseases initiative through funding provided by USAID . The Drugs for Neglected Diseases initiative (DNDi) is grateful to the following donors for funding part of this work: the Bill & Melinda Gates Foundation , USA (Grant no. OPP1111431 ) and the US Agency For International Development (USAID). The contents are the responsibility of the Drugs for Neglected Diseases initiative and do not necessarily reflect the views of the donors. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Funding Information:
Part of the work described in this paper was funded by former Celgene, currently Bristol Myers Squibb (BMS) and New England Biolabs. NAH, SC, and VK are former employees of BMS. GH is an employee of BMS. JZ is a former employee of Celgene. ZL and CC are employees of New England Biolabs. Work by SG, ST, AE, MK, N L-V, CM, AH, SS, and MH was funded by the Drugs for Neglected Diseases initiative through funding provided by USAID. The Drugs for Neglected Diseases initiative (DNDi) is grateful to the following donors for funding part of this work: the Bill & Melinda Gates Foundation, USA (Grant no. OPP1111431) and the US Agency For International Development (USAID). The contents are the responsibility of the Drugs for Neglected Diseases initiative and do not necessarily reflect the views of the donors. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.We gratefully acknowledge the former Celgene San Diego DMPK department and the CLMD group for their kind support. ZL and CC gratefully acknowledge support from Don Comb and New England Biolabs.
Funding Information:
We gratefully acknowledge the former Celgene San Diego DMPK department and the CLMD group for their kind support. ZL and CC gratefully acknowledge support from Don Comb and New England Biolabs .
Publisher Copyright:
© 2022 The Authors
PY - 2022/8
Y1 - 2022/8
N2 - Filarial diseases, including lymphatic filariasis and onchocerciasis, are considered among the most devastating of all tropical diseases, affecting over 86 million people worldwide. To control and more rapidly eliminate onchocerciasis requires treatments that target the adult stage of the parasite. Drug discovery efforts are challenged by the lack of preclinical animal models using the human-pathogenic filariae, requiring the use of surrogate parasites for Onchocerca volvulus for both ex vivo and in vivo evaluation. Herein, we describe a platform utilizing phenotypic ex vivo assays consisting of the free-living nematode Caenorhabditis elegans, microfilariae and adult filariae of the bovine filariae Onchocerca lienalis and Onchocerca gutturosa, respectively, as well as microfilariae and adult filariae of the feline filariae Brugia pahangi, the rodent filariae Litomosoides sigmodontis and the human-pathogenic filariae Brugia malayi to assess activity across various surrogate parasites. Utilization of those surrogate nematodes for phenotypic ex vivo assays in order to assess activity across various parasites led to the successful establishment of a screening cascade and identification of multiple compounds with potential macrofilaricidal activity and desirable physicochemical, MW = 200–400 and low lipophilicity, logP <4, and pharmacokinetic properties, rat and human liver S9 stability of ≥70% remaining at 60 min, and AUC exposures above 3 μM h. This platform demonstrated the successful establishment of a screening cascade which resulted in the discovery of potential novel macrofilaricidal compounds for futher drug discovery lead optimization efforts. This screening cascade identified two distinct chemical series wherein one compound produced a significant 68% reduction of adult Litomosoides sigmodontis in the mouse model. Successful demonstration of efficacy prompted lead optimization medicinal chemistry efforts for this novel series.
AB - Filarial diseases, including lymphatic filariasis and onchocerciasis, are considered among the most devastating of all tropical diseases, affecting over 86 million people worldwide. To control and more rapidly eliminate onchocerciasis requires treatments that target the adult stage of the parasite. Drug discovery efforts are challenged by the lack of preclinical animal models using the human-pathogenic filariae, requiring the use of surrogate parasites for Onchocerca volvulus for both ex vivo and in vivo evaluation. Herein, we describe a platform utilizing phenotypic ex vivo assays consisting of the free-living nematode Caenorhabditis elegans, microfilariae and adult filariae of the bovine filariae Onchocerca lienalis and Onchocerca gutturosa, respectively, as well as microfilariae and adult filariae of the feline filariae Brugia pahangi, the rodent filariae Litomosoides sigmodontis and the human-pathogenic filariae Brugia malayi to assess activity across various surrogate parasites. Utilization of those surrogate nematodes for phenotypic ex vivo assays in order to assess activity across various parasites led to the successful establishment of a screening cascade and identification of multiple compounds with potential macrofilaricidal activity and desirable physicochemical, MW = 200–400 and low lipophilicity, logP <4, and pharmacokinetic properties, rat and human liver S9 stability of ≥70% remaining at 60 min, and AUC exposures above 3 μM h. This platform demonstrated the successful establishment of a screening cascade which resulted in the discovery of potential novel macrofilaricidal compounds for futher drug discovery lead optimization efforts. This screening cascade identified two distinct chemical series wherein one compound produced a significant 68% reduction of adult Litomosoides sigmodontis in the mouse model. Successful demonstration of efficacy prompted lead optimization medicinal chemistry efforts for this novel series.
UR - http://www.scopus.com/inward/record.url?scp=85133909820&partnerID=8YFLogxK
U2 - 10.1016/j.ijpddr.2022.06.002
DO - 10.1016/j.ijpddr.2022.06.002
M3 - Article
C2 - 35834918
AN - SCOPUS:85133909820
SN - 2211-3207
VL - 19
SP - 89
EP - 97
JO - International Journal for Parasitology: Drugs and Drug Resistance
JF - International Journal for Parasitology: Drugs and Drug Resistance
ER -