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Targeted therapeutics against filoviral hemorrhagic fever

Award Number: F30AI136410
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 07/30/2018
PERIOD OF PERFORMANCE END DATE: 07/29/2022

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Targeted therapeutics against filoviral hemorrhagic fever - ABSTRACT Among the most devastating causes of non-traumatic hemorrhage are the Filoviruses, including Ebola and Marburg. Fatality rates from hemorrhage by infection with either of these viruses can exceed 90%. Their outbreak potential was underscored by the 2013-2016 Ebola epidemic in West Africa, which grew from one infected toddler to over 28,000 cases and claimed ~11,000 lives. In acute filovirus infections, patients often develop endothelial leakage and disseminated intravascular coagulation. This vascular disruption, combined with severe diarrhea and vomiting, can progress to profound hypovolemia, hepatic and renal failure. Ebola and Marburg viruses express a single surface glycoprotein (GP) required for host cell infection. Following macropinocytotic uptake, filovirus infection occurs by GP binding to domain C of the endosomal Niemann-Pick C1 (NPC1-C) receptor. The ZMapp antibody cocktail is one proposed treatment for Ebola virus, but to date there are no approved safe and effective antibody or small molecule inhibitors for any other filovirus infection. To address the need for improved treatment options for these pathogens, I will use structure/function analysis to characterize the mechanism of two promising classes of therapeutic candidates that block receptor binding and are broadly reactive. The first class consists of neutralizing antibodies from a human Marburg survivor that block infection by binding conserved receptor-binding sites on GP. MR191 and MR72 are both potent monoclonal antibodies that target Marburg, but MR72 is unique in its broad filovirus cross-reactivity. Last year I determined the crystal structure of MR191 in complex with Marburg virus GP and grew crystals of a MR72- MARV GP complex. Here, I propose to solve the MR72-GP complex structure, and compare antibody-GP contacts to determine critical interaction sites and how MR72 achieves cross-reactivity. Since MR191 showed lifesaving potential in nonhuman primates and is a possible therapeutic for humans, I will also evaluate MR191 escape mutants, which could be used to assess its potential against emergent viral strains. The second class includes small molecule compounds targeting the NPC1 receptor. I will determine structures of two candidate small molecule inhibitors in complex with NPC1-C, and use Ebola GP and other filovirus GPs pseudotyped onto Vesicular Stomatitis Virus to assess whether these compounds inhibit viral entry. In this focused research plan, I will thus use crystals and reagents already in hand to approach treatment of Ebola and Marburg virus disease from two angles: immunotherapy against the receptor-binding site and small molecule therapy against the receptor. This work will be critical for understanding the inhibitory mechanisms of these therapeutic molecules, and will help guide development of safe and effective therapeutics for future outbreaks. This proposal will complement my clinical training in global infectious disease in San Diego and Uganda.


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: 2023 ( Subtotal = $0 )
2023	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	6	5/15/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = -$6,749 )
2022	2020	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	4	4/22/2022	NON-COMPETING CONTINUATION	$0
2022	2019	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	002	3	4/22/2022	NON-COMPETING CONTINUATION	-$6,749
2022	2018	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	4/22/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = -$6,749

Issue Date FY: 2021 ( Subtotal = $32,422 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	002	6	7/16/2021	NON-COMPETING CONTINUATION	$41,729
2021	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	5	6/16/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$41,213
2021	2020	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	4	6/16/2021	NON-COMPETING CONTINUATION	-$50,520
														Subtotal = $32,422

Issue Date FY: 2020 ( Subtotal = $50,520 )
2020	2020	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	4	6/10/2020	NON-COMPETING CONTINUATION	$50,520
														Subtotal = $50,520

Issue Date FY: 2019 ( Subtotal = $32,016 )
2019	2019	LA JOLLA INSTITUTE FOR ALLERGY AND IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	002	3	7/9/2019	NON-COMPETING CONTINUATION	$32,016
2019	2018	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	1	5/13/2019	NEW	-$6,081
2019	2018	LA JOLLA INSTITUTE FOR ALLERGY AND IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	2	5/13/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$6,081
														Subtotal = $32,016

Issue Date FY: 2018 ( Subtotal = $31,524 )
2018	2018	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	1	7/25/2018	NEW	$31,524
2018	2018	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	1	7/25/2018	NEW	$0
														Subtotal = $31,524

Grand Total All Awards = $139,733

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Targeted therapeutics against filoviral hemorrhagic fever

Award Number: F30AI136410

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 07/30/2018

PERIOD OF PERFORMANCE END DATE: 07/29/2022

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