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Structural Analysis and Inhibitor Optimization of Cryptosporidium n-myristoyltransferase for Drug Discovery

Award Number: R01AI155536
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. In contrast to other Apicomplexans (such as Plasmodium or Toxoplasma), there is no required insect vector or animal host, since parasites can be transferred directly from human to human through the fecal-oral route. Despite the high incidence and significant impact on malnourished children, there are no effective treatments for cryptosporidiosis. We had previously screened the GSK Tres Cantos proprietary library of ~2 million compounds against P. falciparum N-myristoyltransferase (NMT). NMT is an enzyme which transfers myristate, a 14-carbon fatty acid, to the N-terminal glycine residue of proteins co-translationally, which 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. We hypothesized that NMT high-throughput screening (HTS) hits effective against Plasmodium would also be active against Cryptosporidium and tested the top eight hits against Cryptosporidium parvum NMT (CpNMT). Of those top eight hits, three were effective against the purified enzyme and one showed activity against the parasite in vitro. A follow-on synthetic chemistry and structure- based drug design program further developed these hits into a lead series (called Series-2) of highly effective (~10nM IC50) inhibitors with 500-1000 X selectivity over the human enzyme. The two most promising leads from the Series-2 scaffold were then tested in a mouse model of infection and found that both molecules completely cleared infection. These data serve to chemically validate NMT as a druggable target for the treatment of Cryptosporidiosis. In this proposal we intend to further develop lead compounds in order to improve drug-like characteristics in preparation for preclinical drug development.


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: 2025 ( Subtotal = $800,512 )
2025	2025	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	5	11/6/2024	NON-COMPETING CONTINUATION	$800,512
														Subtotal = $800,512

Issue Date FY: 2024 ( Subtotal = $852,908 )
2024	2024	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	4	11/16/2023	NON-COMPETING CONTINUATION	$767,617
2024	2024	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	001	4	5/15/2024	NON-COMPETING CONTINUATION	$85,291
														Subtotal = $852,908

Issue Date FY: 2023 ( Subtotal = $829,484 )
2023	2023	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	3	11/1/2022	NON-COMPETING CONTINUATION	$829,484
														Subtotal = $829,484

Issue Date FY: 2022 ( Subtotal = $829,484 )
2022	2022	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	2	10/13/2021	NON-COMPETING CONTINUATION	$829,484
														Subtotal = $829,484

Issue Date FY: 2021 ( Subtotal = $850,984 )
2021	2021	SEATTLE CHILDREN'S HOSPITAL	4800 SAND PT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	1	11/13/2020	NEW	$850,984
														Subtotal = $850,984

Grand Total All Awards = $4,163,372

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Structural Analysis and Inhibitor Optimization of Cryptosporidium n-myristoyltransferase for Drug Discovery

Award Number: R01AI155536

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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