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Structural Analysis and inhibitor optimization of Cryptosporidium n-myristoyltransferase for drug discovery

Award Number: R21AI137815
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract Each year over 525,000 children under age five are killed by diarrhea caused by infectious disease. Cryptosporidiosis, the second most frequent cause of childhood diarrhea, is an infection caused by colonization of the intestines by the eukaryotic parasites, Cryptosporidium parvum or C. hominis, and particularly damages and kills malnourished children. Despite the high incidence and significant impact on malnourished children, there are no effective preventive or therapeutic treatments for cryptosporidiosis in this population. N-myristoyltransferase (NMT) is an enzyme which transfers myristate, a 14-carbon fatty acid, to the N-terminus of glycyl-peptides and contributes to targeting the substrate protein to membrane regions. NMT has been validated as a drug target in fungal and parasitic diseases, including malaria and leishmaniasis. Our collaborators previously screened the GSK Tres Cantos proprietary library of 3 million compounds against P. falciparum NMT and identified 8 unique clusters of compounds with anti NMT activity. We hypothesized that NMT inhibitors effective against Plasmodium would also be active against Cryptosporidium. To test this hypothesis, we screened representative compounds from each cluster for their ability to inhibit Cryptosporidium NMT (CpNMT) activity (using an in vitro enzymatic assay) and parasite growth (using a cell culture assay). We have identified three different scaffolds effective at inhibiting CpNMT, one of which was also effective at preventing replication in cell culture. Based on our preliminary results, we hypothesize that inhibitors targeting CpNMT will result in parasite clearance in animal models of infection. We propose to test our hypothesis by examining our best hit compounds in a mouse model of infection. We will first expand our library of three hit scaffolds by synthesizing and acquiring structurally related compounds using a structure-guided approach. We will progress the compounds through a screening cascade composed of in vitro assays to characterize the compounds and determine structure activity relationship (SAR) profiles of the hit scaffolds. Select compounds will then be tested in an animal model of infection to determine if the NMT inhibitors are active in vivo. In parallel, we will develop structural biology tools for determining the mode of binding and crystal structure of bound compounds to the CpNMT enzyme.


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: 2022 ( Subtotal = -$380 )
2022	2019	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	001	2	6/29/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2019	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	2	6/29/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$380
														Subtotal = -$380

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	2	6/11/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $209,219 )
2019	2019	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	003	2	4/30/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$123,152
2019	2019	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	001	2	11/21/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$209,219
2019	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	1	11/21/2018	NEW	$0
2019	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	002	1	4/30/2019	NEW	-$123,152
														Subtotal = $209,219

Issue Date FY: 2018 ( Subtotal = $282,210 )
2018	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	1	12/21/2017	NEW	$282,210
														Subtotal = $282,210

Grand Total All Awards = $491,049

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Structural Analysis and inhibitor optimization of Cryptosporidium n-myristoyltransferase for drug discovery

Award Number: R21AI137815

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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