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Characterization of Enterovirus 68 3C Protease For the Development of Robust and Potent Direct-Acting Antiviral Inhibitors

Award Number: F30AI181515
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/15/2023
PERIOD OF PERFORMANCE END DATE: 12/14/2028

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Characterization of Enterovirus 68 3C Protease For the Development of Robust and Potent Direct-Acting Antiviral Inhibitors - Project Abstract: Certain viruses in the picornaviridae family, specifically enterovirus-D68 (EV68), have emerged as global health concerns over the last decade with severe symptomatic infections with EV68 able to result in long lasting neurological deficits and death. There are currently no US Food and Drug Administration approved drugs for any non-polio enterovirus, highlighting the need to develop strategies against these lethal enteroviral strains. One particularly attractive class of potential drugs are small molecules inhibitors, which can act as direct-acting antiviral (DAA) inhibitors towards the conserved active site of EV68 3C protease. This main viral protease is a cysteine protease conserved in the 3C family, responsible for cleaving eight sites along the viral polyprotein, which is essential for viral propagation. DAAs designed to target 3C proteases can potentially achieve robust inhibition across enterovirus species. However, as drug resistance in viruses can be prevalent, it is paramount to design inhibitors less susceptible to resistance mutations. It was demonstrated previously in the Schiffer Lab that when bound to protease, viral substrates occupy a conserved three-dimensional volume called the substrate envelope. It was also demonstrated that inhibitors that extend beyond the substrate envelope are more susceptible to drug resistance mutations. By utilizing the substrate envelope and cocrystal structures of the proteases, DAAs designed to fit within the three-dimensional consensus volume as naturally occurring substrates will interact primarily with functionally important residues and be less susceptible to drug resistance mutations. The central hypothesis of this proposal is that cocrystallization of EV68 3C protease with its natural substrates will enable the calculation of the substrate envelope to inform on substrate specificity, which will also aid in the design of robust pan-3C-protease inhibitors. In Aim 1, I will determine the cocrystal structures of EV68 3C protease bound to viral substrates. I will then use these structures to elucidate the molecular mechanism of substrate specificity for EV68 3C protease and calculate the substrate envelope. These data will aid in small- molecule design to create DAAs with improved resilience to mutations that can confer drug resistance. In Aim 2, I will design and test novel DAAs that target EV68 3C protease. I will first characterize previously designed inhibitors for other 3C and 3C-like proteases with the substrate envelope to establish a starting compound based on potency. Inhibitors based on the scaffold will be designed, synthesized, and tested in a FRET-based enzyme inhibition assay. Crystallization of novel potent compounds with EV68 3C and their characterization within the substrate envelope will assess inhibitors’ susceptibility to drug resistance mutations. Overall, this study aims to develop a robust, novel compounds with resistance-thwarting protease inhibition against the emerging pathogen that is EV68.


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: 2026 ( Subtotal = $58,114 )
2026	2026	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	3	12/16/2025	NON-COMPETING CONTINUATION	$57,538
2026	2026	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	001	3	4/2/2026	NON-COMPETING CONTINUATION	$576
														Subtotal = $58,114

Issue Date FY: 2025 ( Subtotal = $54,538 )
2025	2025	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	2	11/29/2024	NON-COMPETING CONTINUATION	$53,974
2025	2025	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	001	2	8/4/2025	NON-COMPETING CONTINUATION	$564
														Subtotal = $54,538

Issue Date FY: 2024 ( Subtotal = $53,974 )
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	001	1	12/15/2023	NEW	$0
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	002	1	5/8/2024	NEW	$1,280
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	1	12/15/2023	NEW	$52,694
														Subtotal = $53,974

Grand Total All Awards = $166,626

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Characterization of Enterovirus 68 3C Protease For the Development of Robust and Potent Direct-Acting Antiviral Inhibitors

Award Number: F30AI181515

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/15/2023

PERIOD OF PERFORMANCE END DATE: 12/14/2028

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