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Investigation of ATV-Based Heterobifunctional Degraders to Combat Growing HIV-1 PR Inhibitor Resistance

Award Number: R21AI170213
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: 08/04/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Investigation of ATV-Based Heterobifunctional Degraders to Combat Growing HIV-1 PR Inhibitor Resistance - PROJECT SUMMARY/ABSTRACT Heterobifunctional targeted protein degraders (TPDs) offer advantages over traditional occupancy-based inhibitors including a unique catalytic mechanism of action (MOA), greater target selectivity, and a reduced probability for resistance development. TPDs are known to effectively target not only cytosolic proteins, but also nuclear and membrane-bound proteins. This therapeutic modality shows great promise for treating drug-resistant cancers and autoimmune diseases but has seen only limited application in antiviral drug discovery. HIV-1 protease (PR) is essential for proteolytic cleavage of Gag and Gag-Pol polyproteins and, thus, virion maturation and infectivity. Gag-Pol forms dynamic dimers at plasma membrane assembly/budding sites, allowing the embedded precursor PR to dimerize as a prerequisite for auto-processing. We identified precursor PR/Gag-Pol as a promising target for protease inhibitor (PI)-based TPDs. The widely used HIV-1 PI, Atazanavir (ATV), is amenable to conjugation with linkers and ubiquitin E3 ligase recruiting ligands to serve as prototype HIV-1 TPDs. Importantly, ATV inhibits activity of mature PR as well as autoprocessing of precursor PR/Gag-Pol during the assembly and budding processes. The OBJECTIVE of this study is to show proof-of-concept that HIV-1 Gag- Pol assembling on the inner leaflet of the plasma membrane can be targeted for aberrant ubiquitination, degradation, and/or inhibition, thereby impairing HIV infectivity. Importantly, due to TPDs’ established MOA, even low-affinity Gag-Pol/TPD interactions are likely to lead to impaired Gag-Pol function. Thus, we pose the HYPOTHESIS that novel ATV-based TPDs will not only augment the inhibition of ATV-sensitive HIV-1 strains compared to ATV, but also exhibit increased and broader biological activity against drug-resistant variants. The objective of AIM 1 is to design and synthesize ATV-based TPDs built on state-of-the-art computational methods and predictive physicochemical properties currently accepted for in vivo active TPDs. Our approach will feature a modular TPD design to establish the appropriate ATV attachment point, E3 ligase recruiter, and length and composition of linker required for HIV-1 Gag-Pol ubiquitination/proteasomal degradation. The goal of AIM 2 is to provide proof-of-concept that ATV-TPDs exert superior activity versus ATV against wild type and PI-resistant HIV-1 strains. We will systematically screen four series of novel ATV-TPD for activity in vitro, in single-round infectivity, and in multi-round replication assays to identify the most promising ATV-TPD candidates. The latter will be tested in complementary limited-scope mechanistic studies, including comparing ATV-TPDs with analogs bearing inactive E3-ligase ligands, to probe if antiviral activity is consistent with the proposed MOA. The IMPACT will be TPDs targeting HIV-1 Gag-Pol and precursor PR that limit infectivity and replication through a mechanism distinct from occupancy-based HIV-1 PI. This will spur the future development of efficacious regimens against PI-resistant HIV strains with reduced susceptibility for resistance development.


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: 2026 ( Subtotal = $0 )
2026	2023	UNIVERSITY OF ALABAMA	801 UNIVERSITY BLVD	TUSCALOOSA	AL	35401	TUSCALOOSA	USA	Allergy and Infectious Diseases Research	000	2	2/12/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $196,382 )
2023	2023	UNIVERSITY OF ALABAMA	301 ROSE ADMIN BLDG	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Allergy and Infectious Diseases Research	001	2	7/25/2023	NON-COMPETING CONTINUATION	$196,382
2023	2022	UNIVERSITY OF ALABAMA	301 ROSE ADMIN BLDG	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Allergy and Infectious Diseases Research	000	1	11/17/2022	NEW	$0
														Subtotal = $196,382

Issue Date FY: 2022 ( Subtotal = $227,034 )
2022	2022	UNIVERSITY OF ALABAMA	301 ROSE ADMIN BLDG	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Allergy and Infectious Diseases Research	000	1	8/4/2022	NEW	$227,034
														Subtotal = $227,034

Grand Total All Awards = $423,416

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Investigation of ATV-Based Heterobifunctional Degraders to Combat Growing HIV-1 PR Inhibitor Resistance

Award Number: R21AI170213

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: 08/04/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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