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Development of non-sedative, parasite-selective benzodiazepines to treat the neglected tropical disease schistosomiasis

Award Number: R21AI146540
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Development of non-sedative, parasite-selective benzodiazepines to treat the neglected tropical disease schistosomiasis - ABSTRACT: The neglected tropical disease schistosomiasis is caused by parasitic blood flukes that infect >230 million people worldwide. Current treatment is reliant on just one drug, praziquantel (PZQ). PZQ is ineffective against recently acquired parasites that have not reached sexual maturity. PZQ also does not kill schistosomes directly. These drawbacks, and the prospect of emerging treatment-resistant parasite strains, highlight the need for alternative therapies to control schistosomiasis. The long-term goal is to identify improved anti-schistosomal drugs. Therefore, this proposal will investigate an alternative group of compounds with proven anti-parasitic activity, benzodiazepines. Benzodiazepine leads are effective at treating schistosomiasis but have high affinity for the human GABAARs that cause sedation. The overall objective of this application is to identify derivatives of a schistocidal benzodiazepine, meclonazepam, that retain anti- parasitic activity and lack affinity for sedation-causing GABAAR sub-types. The central hypothesis is that that benzodiazepine therapies with decreased engagement of host GABAARs will minimize sedation and retain schistocidal activity. The rationale for this project is that while host sedation is driven by drug action at the α1GABAAR, schistosome genomes lack GABAARs entirely. Therefore, GABAARs cannot account for the anti- parasitic effects of benzodiazepines. Instead, preliminary data indicates that meclonazepam acts on parasite Ca2+ channels. Since the ‘on-target’ parasite receptor and ‘off-target’ host receptor for this drug are distinct, it should be possible to develop treatments with improved selectivity. This will be done by pursuing two specific aims: 1) Develop analogs of meclonazepam with decreased activity at mammalian α1GABAARs. 2) Block sedation in vivo by admixture of meclonazepam with α1GABAAR antagonists. Under the first aim, we will synthesize meclonazepam analogs and screen these and other sub-type selective benzodiazepines in binding assays against mammalian GABAARs. Compounds with decreased GABAAR affinity will then be screened against schistosomes to identify parasite-selective derivatives. Finally, schistocidal ligands will be screened in murine model of schistosomiasis to assess efficacy benchmarked relative to meclonazepam. In the second aim, we will assess the in vivo sedative effects of meclonazepam (as well as hits from Aim 1) and the blockade of sedation by α1GABAAR-selective antagonists. The rotarod test will be used to determine the sedating dose of each compound, which will then be administered in mixture with varying ratios of antagonists to determine an admixture that admixture clears parasites with minimized side effects. The research proposed is significant because it will advance new schistocidal leads – no drug to treat schistosomiasis has been FDA approved since 1982. This research is innovative, combining Dr. Chan’s expertise in parasitology with the medicinal chemistry expertise of Dr. Cook, an expert in fundamental properties and pharmacology of GABAAR subtypes.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = -$395 )
2024	2021	UNIVERSITY OF WISCONSIN SYSTEM	800 ALGOMA BLVD	OSHKOSH	WI	54901	WINNEBAGO	USA	Allergy and Infectious Diseases Research	000	5	1/23/2024	NON-COMPETING CONTINUATION	-$395
														Subtotal = -$395

Issue Date FY: 2023 ( Subtotal = -$48,919 )
2023	2020	UNIVERSITY OF WISCONSIN SYSTEM	800 ALGOMA BLVD	OSHKOSH	WI	54901	WINNEBAGO	USA	Allergy and Infectious Diseases Research	000	2	5/15/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$48,919
														Subtotal = -$48,919

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	UNIVERSITY OF WISCONSIN SYSTEM	800 ALGOMA BLVD	OSHKOSH	WI	54901	WINNEBAGO	USA	Allergy and Infectious Diseases Research	003	5	5/12/2022	NON-COMPETING CONTINUATION	$165,786
2022	2021	UNIVERSITY OF WISCONSIN SYSTEM	800 ALGOMA BLVD	OSHKOSH	WI	54901	WINNEBAGO	USA	Allergy and Infectious Diseases Research	002	3	5/12/2022	NON-COMPETING CONTINUATION	-$165,786
2022	2020	UNIVERSITY OF WISCONSIN SYSTEM	800 ALGOMA BLVD	OSHKOSH	WI	54901	WINNEBAGO	USA	Allergy and Infectious Diseases Research	001	4	4/19/2022	EXTENSION WITH OR WITHOUT FUNDS	$190,382
2022	2020	UNIVERSITY OF WISCONSIN SYSTEM	800 ALGOMA BLVD	OSHKOSH	WI	54901	WINNEBAGO	USA	Allergy and Infectious Diseases Research	000	2	4/19/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$190,382
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $165,786 )
2021	2021	UNIVERSITY OF WISCONSIN SYSTEM	800 ALGOMA BLVD	OSHKOSH	WI	54901	WINNEBAGO	USA	Allergy and Infectious Diseases Research	000	3	4/1/2021	NON-COMPETING CONTINUATION	$165,786
2021	2020	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Allergy and Infectious Diseases Research	001	1	7/1/2021	NEW	-$48,919
2021	2020	UNIVERSITY OF WISCONSIN SYSTEM	800 ALGOMA BLVD	OSHKOSH	WI	54901	WINNEBAGO	USA	Allergy and Infectious Diseases Research	002	2	7/1/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$48,919
														Subtotal = $165,786

Issue Date FY: 2020 ( Subtotal = $239,301 )
2020	2020	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Allergy and Infectious Diseases Research	000	1	2/7/2020	NEW	$239,301
2020	2020	UNIVERSITY OF WISCONSIN SYSTEM	800 ALGOMA BLVD	OSHKOSH	WI	54901	WINNEBAGO	USA	Allergy and Infectious Diseases Research	002	2	8/18/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$190,382
2020	2020	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Allergy and Infectious Diseases Research	001	1	8/18/2020	NEW	-$190,382
														Subtotal = $239,301

Grand Total All Awards = $355,773

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Development of non-sedative, parasite-selective benzodiazepines to treat the neglected tropical disease schistosomiasis

Award Number: R21AI146540

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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