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Development of HIV capsid-targeting antivirals that affect immune response by modulating capsid stability and have improved resistance profiles

Award Number: R01AI120860
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY The HIV-1 capsid (CA) is a protein that plays a major role in multiple steps of the virus life cycle. During the previous funding cycle we solved the elusive structure of the intact native full length hexameric HIV-1 CA revealing previously unknown molecular details, especially at the 3-fold and 2-fold intra-hexamer interfaces that affect core stability. We also solved >45 CA structures that include mutations that modulate core stability, thus providing the first glimpses of the molecular basis of core stabilization that is critical in designing potential therapeutics. Additional structures were in complex with host factor peptides, or a variety of novel inhibitors. In addition, we synthesized and characterized >220 compounds that target the PF74-binding pocket. Among them are compounds with much higher potency than PF74, and importantly, compounds with improved resistance profile compared to GS-6207, a highly potent CA-targeting drug in clinical trials. In addition to strong CA hexamer stabilizers, we introduced an innovative class of compounds, “destabilizers” of CA hexamers, raising the exciting prospect of core destabilization that may lead to premature capsid uncoating and interferon upregulation. We will use a combination of chemical synthesis, virological, biophysical, and crystallography approaches to synthesize a number of compounds that improve potency through new inter- and intra-protomer interactions; overcome GS-6207 resistance mutations; modulate core stability and upregulate interferon response; enable interactions with CA through innovative mechanisms, including covalent crosslinking. The compounds will be characterized and the structure activity relationship studies will be guided by X-ray crystallography, biophysical studies (time-lapse imaging, thermal shift, assembly kinetics assays) and virological characterization of mechanism of action as well as drug resistance studies. The research will be conducted by the groups of Stefan Sarafianos at Emory Univ (structure, biophysics, virology) and ZQ Wang (chemical synthesis, Univ of Minnesota), Eric Freed at DRP-NCI (virology), and in collaboration with Greg Melikian (imaging). The proposed studies will advance our understanding of the structural basis of core stability, which controls a large number of steps in the virus life cycle. They will also lead to the identification of innovative compound leads with novel “CA-destabilizing” mechanisms of action, high potency, improved resistance profiles, CA-crosslinking functionalities, and improved pharmacological properties.


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 = $534,364 )
2023	2023	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	9	5/15/2023	NON-COMPETING CONTINUATION	$534,364
														Subtotal = $534,364

Issue Date FY: 2022 ( Subtotal = $538,140 )
2022	2022	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	8	5/11/2022	NON-COMPETING CONTINUATION	$538,140
2022	2021	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	002	7	6/30/2022	COMPETING CONTINUATION	$4,298
2022	2019	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	001	6	6/30/2022	NON-COMPETING CONTINUATION	-$4,298
														Subtotal = $538,140

Issue Date FY: 2021 ( Subtotal = $551,383 )
2021	2021	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	7	6/23/2021	COMPETING CONTINUATION	$551,383
														Subtotal = $551,383

Issue Date FY: 2019 ( Subtotal = $446,402 )
2019	2019	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	6	4/17/2019	NON-COMPETING CONTINUATION	$446,402
														Subtotal = $446,402

Issue Date FY: 2018 ( Subtotal = $477,520 )
2018	2018	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	004	5	5/9/2018	NON-COMPETING CONTINUATION	$438,413
2018	2017	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Allergy and Infectious Diseases Research	000	3	2/28/2018	NON-COMPETING CONTINUATION	-$345,852
2018	2017	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Allergy and Infectious Diseases Research	002	3	4/25/2018	NON-COMPETING CONTINUATION	-$100,092
2018	2017	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	001	4	2/28/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$384,959
2018	2017	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	003	4	4/25/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$100,092
														Subtotal = $477,520

Issue Date FY: 2017 ( Subtotal = $506,354 )
2017	2017	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Allergy and Infectious Diseases Research	000	3	5/17/2017	NON-COMPETING CONTINUATION	$506,354
														Subtotal = $506,354

Issue Date FY: 2016 ( Subtotal = $525,350 )
2016	2016	CURATORS OF THE UNIVERSITY OF MISSOURI	5100 Rockhill Road	Kansas City	MO	64110	JACKSON	USA	Allergy and Infectious Diseases Research	001	2	6/3/2016	NON-COMPETING CONTINUATION	$511,509
2016	2016	CURATORS OF THE UNIVERSITY OF MISSOURI	5100 Rockhill Road	Kansas City	MO	64110	JACKSON	USA	Allergy and Infectious Diseases Research	000	1	3/31/2016	SUPPLEMENT FOR EXPANSION	$13,841
														Subtotal = $525,350

Issue Date FY: 2015 ( Subtotal = $465,907 )
2015	2015	CURATORS OF THE UNIVERSITY OF MISSOURI	5100 Rockhill Road	Kansas City	MO	64110	JACKSON	USA	Allergy and Infectious Diseases Research	000	1	6/15/2015	NEW	$465,907
														Subtotal = $465,907

Grand Total All Awards = $4,045,420

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Development of HIV capsid-targeting antivirals that affect immune response by modulating capsid stability and have improved resistance profiles

Award Number: R01AI120860

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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