Discovery of oseltamivir-based novel PROTACs as degraders targeting neuraminidase to combat H1N1 influenza virus

Xu, Zhichao; Liu, Xinjin; Ma, Xiaoyu; Wen-ting, Zou; Chen, Qi; Chen, Feifei; Deng, Xiaofei; Liang, Jinsen; Dong, Chune; Lan, Ke; Wu, Shuwen; Zhou, Hai‐Bing

doi:10.1016/j.cellin.2022.100030

Cited by 35 publications

(27 citation statements)

References 45 publications

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“…Hydrophobic interactions and hydrogen bonds of the synthesized PROTAC molecules with neuraminidase and VHL ligase were involved in the formation of a stable ternary complex. The N-substituted oseltamivir-based PROTACs were more effective than their carboxylate counterparts [ 79 ]. The mechanism of action of oseltamivir-based PROTACs involves the targeting and degradation of neuraminidase via the ubiquitin-proteasome pathway.…”

Section: Protac-based Antiviral Strategiesmentioning

confidence: 99%

“…Inhibition of the neuraminidase activity and its subsequently degradation ensures that the virions synthesized in the host cell do not leave and remain attached to the host cell. These PROTACs were effective against oseltamivir-resistant strains on further evaluation [ 79 ].…”

Section: Protac-based Antiviral Strategiesmentioning

confidence: 99%

“…The evolving genome of a virus makes it challenging for a particular antiviral therapy to function against it for a longer time but also limits the duration of immunity elicited by infection and vaccination. Studies suggest that PROTAC technology can increase the efficacy of existing antiviral therapeutics [ 79 ]. Differently recruited E3 ligases in the ternary complex enable the selection of different target viral proteins with variable specificities.…”

Section: Advantages Of Protac-based Antiviral Strategiesmentioning

confidence: 99%

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Recent Advances in PROTAC-Based Antiviral Strategies

et al. 2023

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Numerous mysteries of cell and molecular biology have been resolved through extensive research into intracellular processes, which has also resulted in the development of innovative technologies for the treatment of infectious and non-infectious diseases. Some of the deadliest diseases, accounting for a staggering number of deaths, have been caused by viruses. Conventional antiviral therapies have been unable to achieve a feat in combating viral infections. As a result, the healthcare system has come under tremendous pressure globally. Therefore, there is an urgent need to discover and develop newer therapeutic approaches against viruses. One such innovative approach that has recently garnered attention in the research world and can be exploited for developing antiviral therapeutic strategies is the PROteolysis TArgeting Chimeras (PROTAC) technology, in which heterobifunctional compounds are employed for the selective degradation of target proteins by the intracellular protein degradation machinery. This review covers the most recent advancements in PROTAC technology, its diversity and mode of action, and how it can be applied to open up new possibilities for creating cutting-edge antiviral treatments and vaccines.

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Section: Protac-based Antiviral Strategiesmentioning

confidence: 99%

Section: Protac-based Antiviral Strategiesmentioning

confidence: 99%

Section: Advantages Of Protac-based Antiviral Strategiesmentioning

confidence: 99%

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Recent Advances in PROTAC-Based Antiviral Strategies

et al. 2023

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“…In the same year, another study described the development of oseltamivir-based PROTACs with anti-H1N1 influenza activity, considering both VHL and CRBN E3 ligase ligands. 76 The best PROTAC 9 ( Figure 4 ), featuring the VHL binder, degraded the neuraminidase (NA) protein through UPS and exhibited potent antiviral activity toward both the wild-type H1N1 virus and an oseltamivir-resistant strain.…”

Section: Protacs In Viral Diseasesmentioning

confidence: 99%

Targeted Protein Degradation for Infectious Diseases: from Basic Biology to Drug Discovery

Chávez

Salerno

Liuzzi

et al. 2022

ACS Bio Med Chem Au

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Targeted protein degradation (TPD) is emerging as one of the most innovative strategies to tackle infectious diseases. Particularly, proteolysis-targeting chimera (PROTAC)-mediated protein degradation may offer several benefits over classical anti-infective small-molecule drugs. Because of their peculiar and catalytic mechanism of action, antiinfective PROTACs might be advantageous in terms of efficacy, toxicity, and selectivity. Importantly, PROTACs may also overcome the emergence of antimicrobial resistance. Furthermore, anti-infective PROTACs might have the potential to (i) modulate "undruggable" targets, (ii) "recycle" inhibitors from classical drug discovery approaches, and (iii) open new scenarios for combination therapies. Here, we try to address these points by discussing selected case studies of antiviral PROTACs and the first-in-class antibacterial PROTACs. Finally, we discuss how the field of PROTAC-mediated TPD might be exploited in parasitic diseases. Since no antiparasitic PROTAC has been reported yet, we also describe the parasite proteasome system. While in its infancy and with many challenges ahead, we hope that PROTAC-mediated protein degradation for infectious diseases may lead to the development of next-generation anti-infective drugs.

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“…Furthermore, interestingly, all the synthesized compounds do not show cytotoxicity towards the normal cells with a concentration up to CC 50 > 50 µM. Docking studies indicated that these ternary complexes showed great hydrogen bonding and hydrophobic interactions between neuraminidase and E3 ligase [ 53 ]. From these above studies, it could be concluded that there are various strategies being evolved to target viral proteins and inhibit their replication.…”

Section: Eukaryotic Systemmentioning

confidence: 99%

A Perspective on Newly Emerging Proteolysis-Targeting Strategies in Antimicrobial Drug Discovery

2022

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Targeted protein degradation is a new aspect in the field of drug discovery. Traditionally, developing an antibiotic includes tedious and expensive processes, such as drug screening, lead optimization, and formulation. Proteolysis-targeting chimeras (PROTACs) are new-generation drugs that use the proteolytic mechanism to selectively degrade and eliminate proteins involved in human diseases. The application of PROTACs is explored immensely in the field of cancer, and various PROTACs are in clinical trials. Thus, researchers have a profound interest in pursuing PROTAC technology as a new weapon to fight pathogenic viruses and bacteria. This review highlights the importance of antimicrobial PROTACs and other similar “PROTAC-like” techniques to degrade pathogenic target proteins (i.e., viral/bacterial proteins). These techniques can perform specific protein degradation of the pathogenic protein to avoid resistance caused by mutations or abnormal expression of the pathogenic protein. PROTAC-based antimicrobial therapeutics have the advantage of high specificity and the ability to degrade “undruggable” proteins, such as nonenzymatic and structural proteins.

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Discovery of oseltamivir-based novel PROTACs as degraders targeting neuraminidase to combat H1N1 influenza virus

Cited by 35 publications

References 45 publications

Recent Advances in PROTAC-Based Antiviral Strategies

Recent Advances in PROTAC-Based Antiviral Strategies

Targeted Protein Degradation for Infectious Diseases: from Basic Biology to Drug Discovery

A Perspective on Newly Emerging Proteolysis-Targeting Strategies in Antimicrobial Drug Discovery

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