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DISCOVERY OF BROAD SPECTRUM DENGUE VIRUS PROTEINASE INHIBITORS

Award Number: R43AI079966
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: 06/11/2008
PERIOD OF PERFORMANCE END DATE: 05/31/2010

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DISCOVERY OF BROAD SPECTRUM DENGUE VIRUS PROTEINASE INHIBITORS - DESCRIPTION (provided by applicant): Over half of the world population is at risk for infection by dengue virus, a mosquito borne member of the Flavivirus family that consists of four distinct serotypes. Approximately 50 to 100 million infections occur annually resulting in an estimated 500,000 cases of life threatening dengue hemorrhagic fever or dengue shock syndrome. Due to the increased incidence and spreading geographic distribution of dengue infection, it is considered to be an emerging disease and is identified by NIAID as a category A priority pathogen. Despite the significant disease burden associated with dengue infection there is presently no approved vaccine or antiviral drug. The goal of this project is to discover and develop antiviral drugs that inhibit dengue virus infection by blocking the proteolytic activity of the dengue virus NS3 protein. The protease is a key enzyme in viral maturation and inhibition of flavivirus protease has been shown to dramatically reduce viral replication. Structure based drug design will provide a rapid path to potent and virus specific protease inhibitors. We will virtually screen the active site with a chemical library. These targets will be examined by molecular modeling through a process of virtual drug screening to find potential inhibitor compounds that will then be tested experimentally in vitro utilizing biochemical assays optimized during the course of the project. A cell based assay will also be used to confirm virus inhibition in a slightly more physiological environment. Compounds that are active versus the Dengue NS3 proteinase of serotype 2 will also be tested versus the other 3 serotypes, in order to identify potential broad spectrum dengue antiviral therapeutics. At the conclusion of Phase I we intend to select at least one lead series with high potency to be optimized toward producing an effective broad spectrum dengue antiviral drug and possible other Flaviviruses during Phase II. PUBLIC HEALTH RELEVANCE: Dengue fever causes more illness and death than any other arboviral disease and is spreading into new geographic areas, with 925,000 cases reported in 2006. No commercial prophylactic or therapeutic is available to treat the disease. Our strategy is to discover and optimize orally available antiviral drugs to prevent and treat Dengue virus infections, with potential broad spectrum activity versus all flaviviruses.


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: 2009 ( Subtotal = $299,960 )
2009	2009	PANTHERA BIOPHARMA LLC	99-193 AIEA HEIGHTS DRIVE	AIEA	HI	96701	HONOLULU	USA	Allergy and Infectious Diseases Research	001	2	6/23/2009	NON-COMPETING CONTINUATION	$299,960
2009	2008	PANTHERA BIOPHARMA LLC	99-193 AIEA HEIGHTS DRIVE	AIEA	HI	96701	HONOLULU	USA	Allergy and Infectious Diseases Research	000	1	11/14/2008	NEW	$0
														Subtotal = $299,960

Issue Date FY: 2008 ( Subtotal = $299,997 )
2008	2008	PANTHERA BIOPHARMA LLC	99-193 AIEA HEIGHTS DRIVE	AIEA	HI	96701	HONOLULU	USA	Allergy and Infectious Diseases Research	000	1	6/10/2008	NEW	$299,997
														Subtotal = $299,997

Grand Total All Awards = $599,957

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DISCOVERY OF BROAD SPECTRUM DENGUE VIRUS PROTEINASE INHIBITORS

Award Number: R43AI079966

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: 06/11/2008

PERIOD OF PERFORMANCE END DATE: 05/31/2010

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