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Small Molecule Inhibitors Against 3C-Like Protease of SARS-CoV-2

Award Number: R01AI161085
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: 08/06/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Small Molecule Inhibitors Against 3C-Like Protease of SARS-CoV-2 - PROJECT SUMMARY Human coronaviruses generally cause the common cold, a mild upper respiratory illness, however, global outbreaks of new human coronavirus infections with severe respiratory disease have periodically emerged from animals. These include Severe Acute Respiratory coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and, most recently, SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19). Currently, there are no licensed vaccines or antiviral drugs against these viruses, underscoring an urgent need for the development of preventive and therapeutic measures against coronaviruses. Coronavirus genomes encode large polyproteins which are processed by a 3C-like protease (3CLpro) and a papain-like protease. Both proteases are essential for viral replication, making them attractive targets for drug development. Our foray in this area has resulted in the discovery of broad-spectrum inhibitors of multiple viruses, including coronaviruses and noroviruses that encode 3CLpro, as well as the first demonstration of clinical efficacy by a feline coronavirus 3CLpro inhibitor. Recently, we have demonstrated that a dipeptidyl series of compounds potently inhibit human coronaviruses, including MERS-CoV and SARS-CoV-2 in cell culture, and display in vivo efficacy in the DPP4-KI mouse model of MERS-CoV infection. The antiviral target of the compounds was validated by obtaining high resolution crystal structures 3CLpro-inhibitor complexes from SARS-CoV, SARS- CoV-2 and MERS-CoV. We hypothesize herein that the identified series can serve as a launching pad for the development of SARS-CoV-2-specific antivirals. The immediate and overarching goal of the proposed studies is to further optimize the pharmacological activity PK parameters of identified lead inhibitors of SARS-CoV-2 3CLpro and the demonstration of in vivo efficacy against SARS-CoV-2. The expected outcome of our studies is the selection of a preclinical candidate (and 1-2 backup compounds) that is well-suited to conducting further preclinical studies, ultimately leading to the development of a COVID-19-specific antiviral therapeutic.


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 = $731,337 )
2025	2025	KANSAS STATE UNIVERSITY	1601 VATTIER STREET	MANHATTAN	KS	66506	RILEY	USA	Allergy and Infectious Diseases Research	000	4	2/12/2025	EXTENSION WITH OR WITHOUT FUNDS	$731,337
														Subtotal = $731,337

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	KANSAS STATE UNIVERSITY	1601 VATTIER STREET	MANHATTAN	KS	66506	RILEY	USA	Allergy and Infectious Diseases Research	000	3	7/2/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $735,037 )
2023	2023	KANSAS STATE UNIVERSITY	1601 VATTIER STREET	MANHATTAN	KS	66506	RILEY	USA	Allergy and Infectious Diseases Research	000	3	5/26/2023	NON-COMPETING CONTINUATION	$735,037
														Subtotal = $735,037

Issue Date FY: 2022 ( Subtotal = $735,037 )
2022	2022	KANSAS STATE UNIVERSITY	2 FAIRCHILD HALL	MANHATTAN	KS	66506	RILEY	USA	Allergy and Infectious Diseases Research	000	2	7/22/2022	NON-COMPETING CONTINUATION	$735,037
														Subtotal = $735,037

Issue Date FY: 2021 ( Subtotal = $774,037 )
2021	2021	KANSAS STATE UNIVERSITY	2 FAIRCHILD HALL	MANHATTAN	KS	66506	RILEY	USA	Allergy and Infectious Diseases Research	000	1	8/6/2021	NEW	$774,037
														Subtotal = $774,037

Grand Total All Awards = $2,975,448

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Small Molecule Inhibitors Against 3C-Like Protease of SARS-CoV-2

Award Number: R01AI161085

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: 08/06/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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