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Targeting the UL37 deamidase to impede HSV-1 infection.

Award Number: R21AI180537
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: 05/14/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Targeting the UL37 deamidase to impede HSV-1 infection. - ABSTRACT Herpesviruses are ubiquitous human pathogens worldwide. Though herpesvirus infections are often asymptomatic in normal individuals, they cause significant morbidity and mortality in immune-compromised individuals. Antivirals have been successfully developed to target the viral thymidine kinase for the past nearly half-century. In the presence of such antivirals, drug- resistance of herpes simplex viruses (HSV), including HSV-1 and HSV-2, is rapidly emerging, particularly in those immune-compromised individuals such as AIDS patients. Thus, new antivirals are desperately needed to cope with the dire situation. We have previously identified the HSV-1 UL37 deamidase that deamidates and inactivates cytosolic RIG-I and cGAS, thereby muting host innate immune defense. The enzymatic activity of UL37 represents an “Achilles heel” that can be targeted to restore host immune defense. Continuing our original discoveries on protein deamidation, we synthesized series of glutamine analogues to identify inhibitors of selected protein deamidases. In this study, we have identified three lead compounds that selectively inhibit UL37-mediated protein deamidation, but not those mediated by cellular deamidases. Ground on these preliminary results, we will characterize the mode of action of these UL37 inhibitors in protein deamidation and innate immune response during HSV-1 infection. We will further employ a combination of mass spectrometry, structural and pharmacological analysis to improve these lead compounds via iterative synthesis and functional assays. The resulted best inhibitors will be assessed by pharmacokinetics and pharmacodynamic studies as well as antiviral efficacy using mouse model. This pilot study will not only provide proof-of-concept to counteract HSV-1 infection via inhibiting a viral deamidase and restoring host immune defense, but also develop important tools that enable further investigation into protein deamidation in fundamental biological processes.


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 = $201,275 )
2025	2025	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	3/6/2025	NON-COMPETING CONTINUATION	$201,275
														Subtotal = $201,275

Issue Date FY: 2024 ( Subtotal = $248,875 )
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	5/14/2024	NEW	$223,988
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Allergy and Infectious Diseases Research	001	1	9/11/2024	NEW	$24,887
														Subtotal = $248,875

Grand Total All Awards = $450,150

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Targeting the UL37 deamidase to impede HSV-1 infection.

Award Number: R21AI180537

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: 05/14/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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