Antiviral PROTACs: Opportunity borne with challenge

Liang, Jinsen; Wu, Yihe; Lan, Ke; Dong, Chune; Wu, Shuwen; Li, Shu; Zhou, Hai‐Bing

doi:10.1016/j.cellin.2023.100092

Cited by 26 publications

(17 citation statements)

References 172 publications

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“…Numerous small-molecule PROTACs have advanced into clinical trials, particularly in the realm of targeted cancer therapy. While the utilization of PROTAC technology in antiviral research remains relatively limited, and the pool of developed antiviral PROTAC degraders is small, the concept of PROTAC-induced targeted protein degradation is gaining traction as a novel strategy for the development of next-generation antiviral drugs to combat infectious diseases caused by various viruses. − …”

Section: Discussionmentioning

confidence: 99%

“…These distinctive features position PROTAC as a potential game-changing technology in drug discovery that has been widely explored for degrading various disease-causing proteins. Harnessing these advantages, antiviral PROTACs via targeted protein degradation has been considered as a promising strategy for developing next-generation antiviral drugs to combat infectious diseases. − The antiviral PROTACs would improve resistance profiles to those of traditional inhibitors. , In our ongoing pursuit of COVID-19 drug discovery targeting M Pro , we present the design, synthesis, and evaluation of the first series of small-molecule PROTAC degraders targeting SARS-CoV-2 M Pro . Our work has led to the identification of MPD2 as a potent degrader of M Pro with a DC 50 value of 296 nM, demonstrating promising antiviral activity against various SARS-CoV-2 strains and exhibiting enhanced potency against nirmatrelvir-resistant viruses.…”

Section: Introductionmentioning

confidence: 99%

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Discovery of First-in-Class PROTAC Degraders of SARS-CoV-2 Main Protease

Alugubelli,

Xiao,

Khatua

et al. 2024

J. Med. Chem.

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We have witnessed three coronavirus (CoV) outbreaks in the past two decades, including the COVID-19 pandemic caused by SARS-CoV-2. Main protease (M Pro ), a highly conserved protease among various CoVs, is essential for viral replication and pathogenesis, making it a prime target for antiviral drug development. Here, we leverage proteolysis targeting chimera (PROTAC) technology to develop a new class of small-molecule antivirals that induce the degradation of SARS-CoV-2 M Pro . Among them, MPD2 was demonstrated to effectively reduce M Pro protein levels in 293T cells, relying on a time-dependent, CRBN-mediated, and proteasome-driven mechanism. Furthermore, MPD2 exhibited remarkable efficacy in diminishing M Pro protein levels in SARS-CoV-2-infected A549-ACE2 cells. MPD2 also displayed potent antiviral activity against various SARS-CoV-2 strains and exhibited enhanced potency against nirmatrelvir-resistant viruses. Overall, this proof-of-concept study highlights the potential of targeted protein degradation of M Pro as an innovative approach for developing antivirals that could fight against drug-resistant viral variants.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Discovery of First-in-Class PROTAC Degraders of SARS-CoV-2 Main Protease

Alugubelli,

Xiao,

Khatua

et al. 2024

J. Med. Chem.

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“…By utilization of exosomes as delivery vehicles, pepTACs can be efficiently transported to these reservoirs, improving their effectiveness in curbing HIV infection. The integration of pepTACs with exosome-based delivery systems represents a promising approach to precisely target viral proteins and enhance the therapeutic potential of HIV treatment strategies 75 (Table 2).…”

Section: ■ Exosome-based Chipset Designing For Hiv Detection: Advanci...mentioning

confidence: 99%

Synergizing Proteolysis-Targeting Chimeras and Nanoscale Exosome-Based Delivery Mechanisms for HIV and Antiviral Therapeutics

Mukerjee,

Maitra,

Ghosh

et al. 2024

ACS Appl. Nano Mater.

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The global fight against Human Immunodeficiency Virus (HIV) and related viral infections stands at a pivotal juncture, demanding groundbreaking therapeutic strategies. Facing the challenges of existing antiviral treatments, such as viral resistance and nonspecific actions, this paper unveils a transformative approach. We introduce an innovative synergy between proteolysis-targeting chimeras (PROTACs) and exosome-based delivery mechanisms, heralding an innovative era in combating HIV and similar viral diseases. PROTACs emerge as a trailblazing solution, strategically targeting and decomposing crucial viral proteins, and thus, obstructing viral replication and diminishing pathogenesis. Complementing this, the use of exosome-based delivery systemsnature’s own nanoscale couriersensures the precise and effective transportation of these dynamic chimeras directly to infected cells and viral reservoirs. This synergistic strategy is not just a leap forward in HIV therapy; it represents a paradigm shift in antiviral interventions at large. The path to realizing the full potential of these avant-garde technologies lies in sustained research investments, cross-disciplinary collaborations, and rigorous safety and efficacy trials. By channeling these efforts toward HIV, a cornerstone in global health research, we are not just envisioning but actively forging path-breaking advancements in antiviral therapeutics. This represents more than scientific progress; it is a beacon of hope, promising to significantly uplift the lives of those battling these formidable diseases.

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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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Antiviral PROTACs: Opportunity borne with challenge

Cited by 26 publications

References 172 publications

Discovery of First-in-Class PROTAC Degraders of SARS-CoV-2 Main Protease

Discovery of First-in-Class PROTAC Degraders of SARS-CoV-2 Main Protease

Synergizing Proteolysis-Targeting Chimeras and Nanoscale Exosome-Based Delivery Mechanisms for HIV and Antiviral Therapeutics

Small Molecule Drugs Targeting Viral Polymerases

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