Targeted protein degradation as an antiviral approach

Chakravarty, Antara; Yang, Priscilla L.

doi:10.1016/j.antiviral.2022.105480

Cited by 9 publications

(3 citation statements)

References 117 publications

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“…Nef PROTACs also demonstrate potent antiretroviral activity in HIV-infected primary cells, supporting further development for testing in the context of HIV-1 reservoir reduction in vivo. More broadly, these results encourage the development of PROTACs against viral proteins which are intrinsically difficult to target with traditional occupancy-based approaches (Ahmad et al, 2023;Chakravarty and Yang, 2023).…”

Section: Introductionmentioning

confidence: 86%

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PROTAC-mediated Degradation of HIV-1 Nef Efficiently Restores Cell-surface CD4 and MHC-I Expression and Blocks HIV-1 Replication

Emert-Sedlak,

Tice,

Shi

et al. 2023

Preprint

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The HIV-1 Nef accessory factor is critical to the viral life cycle in vivo where it promotes immune escape of HIV-infected cells and viral persistence. While these features identify Nef as an attractive antiretroviral drug target, Nef lacks enzymatic activity and an active site, complicating development of occupancy-based drugs. Here we describe the development of proteolysis targeting chimeras (PROTACs) for the targeted degradation of Nef. Nef-binding compounds, based on a previously reported hydroxypyrazole core, were coupled to ligands for ubiquitin E3 ligases via flexible linkers. The resulting bivalent PROTACs induced formation of a ternary complex between Nef and the Cereblon E3 ubiquitin ligase, resulting in ubiquitylation of Nef and proteolytic degradation. Nef-directed PROTACs efficiently rescued Nef-mediated MHC-I and CD4 downregulation in T cells and suppressed HIV-1 replication in donor PBMCs. Targeted degradation of Nef is anticipated to reverse all HIV-1 Nef functions and may help restore adaptive immune responses against HIV-1 reservoir cells in vivo.

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Section: Introductionmentioning

confidence: 86%

“…More broadly, these results encourage the development of PROTACs against viral proteins which are intrinsically difficult to target with traditional occupancy-based approaches. 27,28…”

Section: Introductionmentioning

confidence: 99%

PROTAC-mediated Degradation of HIV-1 Nef Efficiently Restores Cell-surface CD4 and MHC-I Expression and Blocks HIV-1 Replication

Emert-Sedlak,

Tice,

Shi

et al. 2023

Preprint

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“…While PROTAC technology has been primarily exploited within the anticancer field [195][196][197], its application in the antiviral area is gaining attention [198][199][200][201]. Specifically, PROTAC compounds may be potentially developed against a broad range of viruses by customizing the recruiting ligands to different viral polymerases.…”

Section: Disease Xmentioning

confidence: 99%

Small Molecule Drugs Targeting Viral Polymerases

Palazzotti,

Sguilla,

Manfroni

et al. 2024

Pharmaceuticals

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Small molecules that specifically target viral polymerases—crucial enzymes governing viral genome transcription and replication—play a pivotal role in combating viral infections. Presently, approved polymerase inhibitors cover nine human viruses, spanning both DNA and RNA viruses. This review provides a comprehensive analysis of these licensed drugs, encompassing nucleoside/nucleotide inhibitors (NIs), non-nucleoside inhibitors (NNIs), and mutagenic agents. For each compound, we describe the specific targeted virus and related polymerase enzyme, the mechanism of action, and the relevant bioactivity data. This wealth of information serves as a valuable resource for researchers actively engaged in antiviral drug discovery efforts, offering a complete overview of established strategies as well as insights for shaping the development of next-generation antiviral therapeutics.

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Tear exosome‐based PROteolysis TArgeting Chimeras nanomedicine for human immunodeficiency virus‐mediated cancer treatment

Mukerjee

2024

Clinical and Translational Dis

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Human Immunodeficiency Virus (HIV) significantly increases the risk of various cancers due to chronic immune suppression and viral oncogenes. Traditional therapies, including antiretroviral therapy (ART), chemotherapy, and radiation, often face limitations such as drug resistance and systemic toxicity. PROteolysis TArgeting Chimeras (PROTACs) have emerged as a promising approach for targeted protein degradation, offering significant advantages over conventional treatments. However, effective delivery remains a challenge. This paper explores the innovative use of tear exosome‐based delivery systems for PROTACs in treating HIV‐mediated cancers. Tear exosomes, due to their natural origin, biocompatibility, and inherent targeting capabilities, present a novel and effective platform for delivering PROTACs, enhancing therapeutic specificity and reducing adverse effects. Integrating the unique properties of tear exosomes with the therapeutic potential of PROTACs could revolutionize the treatment of HIV‐mediated cancers by overcoming current therapeutic challenges and improving patient outcomes.

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Targeted protein degradation as an antiviral approach

Cited by 9 publications

References 117 publications

PROTAC-mediated Degradation of HIV-1 Nef Efficiently Restores Cell-surface CD4 and MHC-I Expression and Blocks HIV-1 Replication

PROTAC-mediated Degradation of HIV-1 Nef Efficiently Restores Cell-surface CD4 and MHC-I Expression and Blocks HIV-1 Replication

Small Molecule Drugs Targeting Viral Polymerases

Tear exosome‐based PROteolysis TArgeting Chimeras nanomedicine for human immunodeficiency virus‐mediated cancer treatment

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