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Review
. 2023 Mar 27;2(3):100092.
doi: 10.1016/j.cellin.2023.100092. eCollection 2023 Jun.

Antiviral PROTACs: Opportunity borne with challenge

Jinsen Liang  1 , Yihe Wu  2 , Ke Lan  3 , Chune Dong  1 , Shuwen Wu  3 , Shu Li  1 , Hai-Bing Zhou  1   2
Affiliations
Review

Antiviral PROTACs: Opportunity borne with challenge

Jinsen Liang et al. Cell Insight. .

Erratum in

  • Corrigendum to previous published articles.
    [No authors listed] [No authors listed] Cell Insight. 2025 Jan 11;4(2):100225. doi: 10.1016/j.cellin.2024.100225. eCollection 2025 Apr. Cell Insight. 2025. PMID: 39881711 Free PMC article.

Abstract

Proteolysis targeting chimera (PROTAC) degradation of pathogenic proteins by hijacking of the ubiquitin-proteasome-system has become a promising strategy in drug design. The overwhelming advantages of PROTAC technology have ensured a rapid and wide usage, and multiple PROTACs have entered clinical trials. Several antiviral PROTACs have been developed with promising bioactivities against various pathogenic viruses. However, the number of reported antiviral PROTACs is far less than that of other diseases, e.g., cancers, immune disorders, and neurodegenerative diseases, possibly because of the common deficiencies of PROTAC technology (e.g., limited available ligands and poor membrane permeability) plus the complex mechanism involved and the high tendency of viral mutation during transmission and replication, which may challenge the successful development of effective antiviral PROTACs. This review highlights the important advances in this rapidly growing field and critical limitations encountered in developing antiviral PROTACs by analyzing the current status and representative examples of antiviral PROTACs and other PROTAC-like antiviral agents. We also summarize and analyze the general principles and strategies for antiviral PROTAC design and optimization with the intent of indicating the potential strategic directions for future progress.

Keywords: Antiviral drugs; Drug resistance; E3 ligase; PROTACs; Virus.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
Schematic diagram of the mechanism of action of PROTACs.
Fig. 2
Fig. 2
A) Development timeline of PROTACs; B) The first small-molecule antiviral PROTAC DGY-08-097 (1), and representative antitumor PROTACs ARV-110 (2), ARV-471 (3), and DT2216 (4) currently in clinical trials.
Fig. 3
Fig. 3
The general life cycle of viruses and targets for antiviral agents.
Fig. 4
Fig. 4
The discovery of an HBV X-protein targeting PROTACs based on peptide.
Fig. 5
Fig. 5
The crystal structure complex of telaprevir with HCV NS3/4A and structures of representative HCV NS3/4A-targeted PROTACs.
Fig. 6
Fig. 6
The discovery of IAV NA-targeted PROTACs based on oseltamivir.
Fig. 7
Fig. 7
A) Discovery of IAV HA-targeted PROTACs; B) The mechanism of action of representative PROTAC V3 (6).
Fig. 8
Fig. 8
The discovery of CDK-targeted anti-HCMV PROTACs.
Fig. 9
Fig. 9
The discovery of an IAV PA degrader based on microbial metabolites.
Fig. 10
Fig. 10
The design strategy of an anti-IAV PROTAC vaccine, and the key sequence that selectively induces M1 protein degradation in conventional cells.
Fig. 11
Fig. 11
Schematic diagram of the mechanism of action of RIBOTACs.
Fig. 12
Fig. 12
The discovery of anti-SARS-CoV-2 RIBOTAC and its mechanism of action.
See this image and copyright information in PMC

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