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Small Molecule Protease Inhibitors against MERS-CoV and Coronaviruses of Pandemic Potential

Award Number: R01AI130092
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/19/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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Small Molecule Protease Inhibitors against MERS-CoV and Coronaviruses of Pandemic Potential - PROJECT SUMMARY Middle East respiratory syndrome coronavirus (MERS-CoV) emerged suddenly in 2012 as the cause of severe respiratory illness in humans. Despite the high mortality rate (~ 40%) and the significant potential for a public health emergency, there are no FDA-approved vaccines or antiviral drugs for MERS. Consequently, there is an urgent and unmet need for the development of small-molecule drugs to control MERS-CoV infection. Furthermore, members of the Merbecovirus and Sarbecovirus subgenera within the Betacoronavirus genus pose a high risk of future spillover into humans. However, efforts to develop general strategies to mitigate the impact of future pandemics have been limited. Coronavirus 3C-like protease (3CLpro) is a well-characterized therapeutic target as it processes most cleavage sites on virus polyproteins and is essential for virus replication. Multiple series of 3CLpro inhibitors with potent activity against MERS-CoV and in vivo efficacy in mouse models were reported by our group. However, these compound series are parenterally administrable with limited oral bioavailability. Hypothesize of this project is that inhibitors exploiting the exquisite stereochemical control and multiple diversity sites afforded by the 1,3,2-oxazaphospholidin-3-one scaffold (series I and II) and decorated with a novel transition state analog endowed with favorable oral bioavailability can serve as a launching pad for the development of orally bioavailable MERS-CoV-specific antivirals. As these inhibitors can engage in binding interactions with the Sn and Sn' pockets of various coronavirus 3CLpros, the scaffold provides a versatile platform for merbecoviruses and sarbecoviruses. Aims of this project are 1) Conduct iterative structure-guided design, synthesis, and multiparameter optimization of inhibitors for MERS-CoV; 2) Conduct biochemical, structural, and virological studies to characterize and prioritize analogs for MERS-CoV 3CLpro and conduct structure-activity relationship studies with the generated series for merbecovirus/sarbecovirus 3CLpros; and 3) Demonstrate in vivo efficacy of optimized leads in a mouse model of MERS-CoV infection. The overarching goal of this project is the identification of an orally bioavailable preclinical candidate and 1-2 backup compounds based on inhibitor series (I and II) for MERS-CoV infection, and the exploration and utilization of the generated inhibitors against the 3CLpros of merbecoviruses and sarbecoviruses.


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 = $733,730 )
2025	2025	KANSAS STATE UNIVERSITY	1601 VATTIER STREET	MANHATTAN	KS	66506	RILEY	USA	Allergy and Infectious Diseases Research	002	7	5/21/2025	NON-COMPETING CONTINUATION	$733,730
2025	2024	KANSAS STATE UNIVERSITY	1601 VATTIER STREET	MANHATTAN	KS	66506	RILEY	USA	Allergy and Infectious Diseases Research	001	6	2/19/2025	COMPETING CONTINUATION	$33,771
2025	2022	KANSAS STATE UNIVERSITY	1601 VATTIER STREET	MANHATTAN	KS	66506	RILEY	USA	Allergy and Infectious Diseases Research	000	5	2/19/2025	NON-COMPETING CONTINUATION	-$33,771
														Subtotal = $733,730

Issue Date FY: 2024 ( Subtotal = $773,323 )
2024	2024	KANSAS STATE UNIVERSITY	1601 VATTIER STREET	MANHATTAN	KS	66506	RILEY	USA	Allergy and Infectious Diseases Research	002	6	9/3/2024	COMPETING CONTINUATION	$73,431
2024	2024	KANSAS STATE UNIVERSITY	1601 VATTIER STREET	MANHATTAN	KS	66506	RILEY	USA	Allergy and Infectious Diseases Research	001	6	7/19/2024	COMPETING CONTINUATION	$699,892
2024	2022	KANSAS STATE UNIVERSITY	1601 VATTIER STREET	MANHATTAN	KS	66506	RILEY	USA	Allergy and Infectious Diseases Research	000	5	11/2/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $773,323

Issue Date FY: 2022 ( Subtotal = $728,584 )
2022	2022	KANSAS STATE UNIVERSITY	2 FAIRCHILD HALL	MANHATTAN	KS	66506	RILEY	USA	Allergy and Infectious Diseases Research	000	5	5/3/2022	NON-COMPETING CONTINUATION	$728,584
														Subtotal = $728,584

Issue Date FY: 2021 ( Subtotal = $730,761 )
2021	2021	KANSAS STATE UNIVERSITY	2 FAIRCHILD HALL	MANHATTAN	KS	66506	RILEY	USA	Allergy and Infectious Diseases Research	000	4	4/22/2021	NON-COMPETING CONTINUATION	$730,761
														Subtotal = $730,761

Issue Date FY: 2020 ( Subtotal = $732,873 )
2020	2020	KANSAS STATE UNIVERSITY	2 FAIRCHILD HALL	MANHATTAN	KS	66506	RILEY	USA	Allergy and Infectious Diseases Research	000	3	4/8/2020	NON-COMPETING CONTINUATION	$732,873
														Subtotal = $732,873

Issue Date FY: 2019 ( Subtotal = $734,924 )
2019	2019	KANSAS STATE UNIVERSITY	2 FAIRCHILD HALL	MANHATTAN	KS	66506	RILEY	USA	Allergy and Infectious Diseases Research	000	2	4/19/2019	NON-COMPETING CONTINUATION	$734,924
														Subtotal = $734,924

Issue Date FY: 2018 ( Subtotal = $775,916 )
2018	2018	KANSAS STATE UNIVERSITY	2 FAIRCHILD HALL	MANHATTAN	KS	66506	RILEY	USA	Allergy and Infectious Diseases Research	000	1	5/10/2018	NEW	$775,746
2018	2018	KANSAS STATE UNIVERSITY	2 FAIRCHILD HALL	MANHATTAN	KS	66506	RILEY	USA	Allergy and Infectious Diseases Research	001	1	5/10/2018	NEW	$170
														Subtotal = $775,916

Grand Total All Awards = $5,210,111

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Small Molecule Protease Inhibitors against MERS-CoV and Coronaviruses of Pandemic Potential

Award Number: R01AI130092

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/19/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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