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Targeting the Structurally Conserved Portal Protein as a Strategy to Develop a First-In-Class Broad-Spectrum Herpesvirus Antiviral Drug, PORT 1

Award Number: R15AI152023
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: 12/01/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Targeting the Structurally Conserved Portal Protein as a Strategy to Develop a First-In-Class Broad-Spectrum Herpesvirus Antiviral Drug, PORT 1 - There are nine human herpesvirus (HHV) pathogens that cause significant worldwide morbidity and mortality with treatment costs in the billions of dollars annually. Their ubiquitous nature contributes to primary infection early in life and most adults permanently harbor one or more latent herpesvirus species. Primary disease ranges from asymptomatic to self-limiting (herpes labialis) to life-threatening (cancer). The PI studies a series of non-toxic, non-nucleoside small molecule antiviral drug candidates (PORT compounds) with a unique mechanism of action: inhibition of viral DNA packaging by targeting the viral portal protein. The proposed studies seek to exploit the remarkable structural and functional relatedness of herpesvirus portals. During herpesvirus genome replication, concatamers of viral dsDNA are cleaved into single length units by a virus-encoded terminase and packaged into procapsids through a channel located at a single capsid vertex - the portal. The portal is absolutely required for viral replication. In all cases, function is highly conserved in that portals are essential for DNA packaging and play a role in releasing viral DNA during infection. Our recent findings, which are the basis of this grant application, show that PORT 1 can prevent viral replication in human and animal species in all three herpesvirus subfamilies (alpha, beta and gamma). The remarkable structural conservation of the portal protein core for all herpesvirus species across all three sub- families may provide an opportunity to develop a broad-spectrum HHV drug. Furthermore, a drug with a completely different mechanism than nucleoside analogs (e.g. acyclovir) would have great clinical value for treating drug resistant herpesviruses. A broad-spectrum anti-herpesviral drug could be used to treat more than one herpesvirus infection at one time – particularly in immunocompromised cancer and transplant patients, and fill the need for alternative or first generation therapies for certain herpesviruses (EBV and CMV). We propose four complementary Aims to further these studies. Aim 1 will include synthesis and testing of PORT 1 in vitro activity against alpha, beta, and gamma herpesviruses. PORT1 mechanism of action will be confirmed via TEM by showing that cells infected by a virus from any HHV subfamily contain only empty capsids. Aims 2-4 were conceptualized based on the hypothesis that PORT 1 exhibits broad-spectrum activity against human and animal herpesviruses. Preliminary data are provided showing that PORT 1 has significant in vitro activity against murine cytomegalovirus and murine gammaherpesvirus 68. These results were not unexpected based on the remarkable structural and functional relatedness of ALL herpesvirus portals. Aims 2-4 will test the in vivo efficacy of the lead broad spectrum PORT 1 compound activity against herpes-viruses from all three subfamilies. In the spirit of the NIH REAP grant mechanism, these studies will provide an exciting, mentored laboratory experience for undergraduate, graduate and medical student researchers.


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 = -$68,037 )
2025	2021	THE CORPORATION OF MERCER UNIVERSITY	1501 MERCER UNIVERSITY DR	MACON	GA	31207	BIBB	USA	Allergy and Infectious Diseases Research	000	1	4/14/2025	NEW	-$68,037
														Subtotal = -$68,037

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	THE CORPORATION OF MERCER UNIVERSITY	1501 MERCER UNIVERSITY DR	MACON	GA	31207	BIBB	USA	Allergy and Infectious Diseases Research	000	1	12/7/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $407,629 )
2021	2021	CORPORATION OF MERCER UNIVERSITY, THE	1501 MERCER UNIVERSITY DR	MACON	GA	31207	BIBB	USA	Allergy and Infectious Diseases Research	000	1	12/1/2020	NEW	$407,629
														Subtotal = $407,629

Grand Total All Awards = $339,592

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Targeting the Structurally Conserved Portal Protein as a Strategy to Develop a First-In-Class Broad-Spectrum Herpesvirus Antiviral Drug, PORT 1

Award Number: R15AI152023

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: 12/01/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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