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Developing High-Throughput Assays for DRACO Broad-Spectrum Antiviral Molecules

Award Number: R56AI106939
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: 08/01/2013
PERIOD OF PERFORMANCE END DATE: 07/31/2015

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Developing High-Throughput Assays for DRACO Broad-Spectrum Antiviral Molecules - DESCRIPTION (provided by applicant): This project's ultimate objective is to develop safe broad-spectrum antiviral therapeutics/prophylactics, since there are currently relatively few therapeutics for viruses, and most which do exist are highly virus- specific or have undesirable side effects. The project's proven Double-stranded RNA Activated Caspase Oligomerizer (DRACO) approach selectively induces apoptosis (cell suicide) in cells containing any viral double-stranded RNA (dsRNA), rapidly killing infected cells without harming uninfected cells. We have previously created a protein DRACO that binds to the cellular procaspase-9 caspase recruitment domain (CARD) to induce apoptosis in the presence of dsRNA. We have demonstrated that this protein DRACO is nontoxic and effective against 15 different viruses in cells and 3 viruses in mice. We now propose to collaborate with the National Screening Laboratory for the Regional Centers of Excellence in Biodefense and Emerging Infectious Diseases (NSRB) at Harvard Medical School in order to develop high-throughput screening assays to identify small chemical molecules that would have similar properties to the large DRACO protein but would be easier to manufacture, store, and use. Our specific aims are to: 1. Develop a simple, reliable primary assay for procaspase-9 CARD binding activity suitable for high- throughput screening of small molecules. In consultation with the NSRB lab, we will develop assays that are fully compatible with high-throughput screening equipment and compound libraries. 2. Develop a counter-screening assay to distinguish molecules that bind to procaspase-9 CARD from molecules that bind to Apaf-1 CARD. This same counter-screening assay can be used to screen out molecules that nonspecifically bind to proteins. 3. Collaborate with the NSRB lab to conduct test runs of both the primary and counter-screening assays using their compound library and robotic high-throughput screening equipment. We will use the results of those test runs to iteratively optimize the assay reagents, conditions, and protocols. The proposed work should advance DRACOs toward ultimate utility as safe, broad-spectrum antiviral therapeutics, filling a large gap in existing therapeutics.


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: 2017 ( Subtotal = -$1 )
2017	2013	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	244 WOOD ST	LEXINGTON	MA	02421	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	1	5/8/2017	NEW	-$1
														Subtotal = -$1

Issue Date FY: 2014 ( Subtotal = $222,987 )
2014	2013	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	1	4/15/2014	NEW	-$225,962
2014	2013	Charles Stark Draper Laboratory, Inc.	555 Technology Sq	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Allergy and Infectious Diseases Research	001	2	4/15/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$448,949
														Subtotal = $222,987

Issue Date FY: 2013 ( Subtotal = $457,987 )
2013	2013	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Allergy and Infectious Diseases Research	002	1	4/15/2014	NEW	-$225,962
2013	2013	Charles Stark Draper Laboratory, Inc.	555 Technology Sq	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Allergy and Infectious Diseases Research	001	2	4/15/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$448,949
2013	2013	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	1	7/30/2013	NEW	$235,000
														Subtotal = $457,987

Grand Total All Awards = $680,973

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Developing High-Throughput Assays for DRACO Broad-Spectrum Antiviral Molecules

Award Number: R56AI106939

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: 08/01/2013

PERIOD OF PERFORMANCE END DATE: 07/31/2015

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