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Ultra-potent HIV capsid inhibitors

Award Number: R01AI157802
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: 09/21/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Ultra-potent HIV capsid inhibitors - Abstract Antiretroviral therapies (ART) have transformed the once deadly HIV/AIDS disease into a manageable, chronic infection. Yet, there are still a number of pressing problems associated with current ARTs, including the necessity of daily administration of HIV-1 medications, suboptimal treatment adherence, and the emergence of drug-resistant viral phenotypes. Therefore, there is a need for developing long-acting antiretroviral agents targeting clinically unexploited viral proteins to mitigate the above problems. HIV-1 capsid protein is a novel, attractive target as its plays multiple essential roles during the virus life cycle. GS-6207 (Lenacapavir, Gilead Sciences) is a recently discovered, first-in-class, long-acting, and ultra- potent HIV-1 capsid inhibitor. Recently completed phase 1 clinical trials (NCT03739866) have suggested advancement of GS-6207 into phase 2/3 clinical trials (NCT04143594/NCT04150068) with a six-month dosing interval. Our research objective is to elucidate structural and mechanistic bases for a highly potent antiviral activity of GS-6207 and exploit the knowledge obtained to develop second-generation inhibitors. For this, we have synthesized and examined the antiviral activities of GS-6207. Consistent with the multifaceted role of capsid in HIV-1 biology, the inhibitor potently (EC50 of ~55 pM) impaired incoming virus and exhibited a second, slightly reduced (EC50 of ~314 pM) antiviral activity during virus egress. Mode-of- action studies of GS-6207 revealed that the inhibitor blocks post-entry steps of infection by stabilizing and thereby preventing functional disassembly of the capsid shell in the cytoplasm of infected cells. In addition, GS-6207 interfered with capsid binding to the cellular HIV-1 cofactors Nup153 and CPSF6 that mediate viral nuclear import and direct integration into gene-rich regions of chromatin. Our x-ray crystallography, cryo-electron microscopy, and hydrogen-deuterium exchange experiments have revealed that GS-6207 tightly binds two adjoining capsid subunits and promotes distal intra- and inter-hexamer interactions that strikingly stabilize the curved capsid lattice. Furthermore, our high-resolution x-ray structure of GS-6207 bound to a capsid hexamer enabled us to map drug-resistant variants in close proximity to the GS-6207 binding site. This information will be critical for rational design of second-generation inhibitors. We propose to extend these studies to better understand the multimodal, exceptionally potent antiviral activity of GS- 6207 during both early and late steps of HIV-1 replication. For this, we will pursue the following three specific aims: Aim 1 will elucidate structural and mechanistic bases for inhibition of post-entry steps of HIV- 1 infection by GS-6207; Aim 2 will dissect underlying mechanisms of inhibition of virus production and maturation by GS-6207; and Aim 3 will investigate the structural basis for viral drug-resistance to GS-6207 and rationally develop second-generation inhibitors with an enhanced barrier to resistance. Taken together, the proposed studies will dissect the multimodal antiviral mechanism of action of GS-6207, provide new insights into the viral biology of capsid, identify key inhibitor-capsid interactions and facilitate optimization of this class of compounds for their clinical use.


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: 2027 ( Subtotal = $0 )
2027	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	000	5	10/19/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2026 ( Subtotal = $3,077,904 )
2026	2026	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	001	6	6/23/2026	COMPETING CONTINUATION	$3,077,904
2026	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	000	5	6/12/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $3,077,904

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	001	5	7/11/2025	NON-COMPETING CONTINUATION	$0
2025	2024	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	000	5	6/5/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $792,015 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	000	5	8/12/2024	NON-COMPETING CONTINUATION	$792,015
														Subtotal = $792,015

Issue Date FY: 2023 ( Subtotal = $792,015 )
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	000	4	8/3/2023	NON-COMPETING CONTINUATION	$792,015
														Subtotal = $792,015

Issue Date FY: 2022 ( Subtotal = $792,015 )
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	000	3	8/4/2022	NON-COMPETING CONTINUATION	$792,015
														Subtotal = $792,015

Issue Date FY: 2021 ( Subtotal = $792,015 )
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	000	2	8/4/2021	NON-COMPETING CONTINUATION	$792,015
														Subtotal = $792,015

Issue Date FY: 2020 ( Subtotal = $819,765 )
2020	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	000	1	9/21/2020	NEW	$819,765
														Subtotal = $819,765

Grand Total All Awards = $7,065,729

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Ultra-potent HIV capsid inhibitors

Award Number: R01AI157802

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: 09/21/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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