Identification of a novel acylthiourea-based potent broad-spectrum inhibitor for enterovirus 3D polymerase in vitro and in vivo

Liu, Xinjin; Xu, Zhichao; Liang, Jinsen; Yu, Lei; Ren, Pengyu; Zhou, Hai‐Bing; Wu, Shuwen; Lan, Ke

doi:10.1016/j.antiviral.2023.105583

Cited by 8 publications

(7 citation statements)

References 43 publications

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“…The design strategy for hydrophobically tagged small molecules is shown in Figure . In the previous study, we identified hit compounds with an acyl thiourea scaffold that exerted anti-influenza activity by inhibiting RdRp function. , To facilitate the novel design of HyT degraders, following numerous rounds of structure–activity relationship (SAR) studies, we selected the potent and most suitable 11 as a POI ligand with potent antiviral activity against A/PR/8/H1N1 (EC 50 = 0.024 ± 0.005 μM). Our studies revealed that alteration of the tert -butyl group on the left side of the acyl thiourea backbone was often accompanied by a decrease in anti-influenza virus activity, while modification of the right amino group was tolerated.…”

Section: Resultsmentioning

confidence: 99%

“…(S)-2-Amino-N (30). tert-Butyl 8-bromooctanoate 26 (2.0 g, 7.17 mmol) was added to the solution of 27 (2.50 g, 5.97 mmol) in MeCN (40 mL), and then K 2 CO 3 (2.47 g, 17.91 mmol) was added and the mixture was stirred at 80 °C for 12 h. The reaction mixture was quenched using water and extracted with ethyl acetate (50 mL × 3).…”

Section: Tert-butyl (R)-(1-((4-(3-(4-(tert-butyl)benzoyl)thioureido)p...mentioning

confidence: 99%

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Novel Acyl Thiourea-Based Hydrophobic Tagging Degraders Exert Potent Anti-Influenza Activity through Two Distinct Endonuclease Polymerase Acidic-Targeted Degradation Pathways

Ma,

Wang,

Chen

et al. 2024

J. Med. Chem.

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The spread of the influenza virus has caused devastating pandemics and huge economic losses worldwide. Antiviral drugs with diverse action modes are urgently required to overcome the challenges of viral mutation and drug resistance, and targeted protein degradation strategies constitute excellent candidates for this purpose. Herein, the first degradation of the influenza virus polymerase acidic (PA) protein using small-molecule degraders developed by hydrophobic tagging (HyT) technology to effectively combat the influenza virus was reported. The SAR results revealed that compound 19b with Boc2–(L)-Lys demonstrated excellent inhibitory activity against A/WSN/33/H1N1 (EC50 = 0.015 μM) and amantadine-resistant strain (A/PR/8/H1N1), low cytotoxicity, high selectivity, substantial degradation ability, and good drug-like properties. Mechanistic studies demonstrated that the proteasome system and autophagic lysosome pathway were the potential drivers of these HyT degraders. Thus, this study provides a powerful tool for investigating the targeted degradation of influenza virus proteins and for antiviral drug development.

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Section: Resultsmentioning

confidence: 99%

Section: Tert-butyl (R)-(1-((4-(3-(4-(tert-butyl)benzoyl)thioureido)p...mentioning

confidence: 99%

Novel Acyl Thiourea-Based Hydrophobic Tagging Degraders Exert Potent Anti-Influenza Activity through Two Distinct Endonuclease Polymerase Acidic-Targeted Degradation Pathways

Ma,

Wang,

Chen

et al. 2024

J. Med. Chem.

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“…The key role of 3D pol in viral replication and its structural and sequence conservation make it a promising target for specific antiviral therapeutics ( 19 , 31 , 226 ). Several compounds that bind to 3D pol active sites to block viral replication have been identified, which markedly reduce the synthesis of viral RNA by interacting with or occupying the 3D pol active sites to inhibit enzyme function ( 227 – 229 ). Therefore, further elucidating the structures and molecular functions of 3D pol is valuable and could be useful for future antiviral treatment of picornaviruses.…”

Section: Discussionmentioning

confidence: 99%

Multiple functions of the nonstructural protein 3D in picornavirus infection

Xu,

Wang,

Cheng

et al. 2024

Front. Immunol.

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3D polymerase, also known as RNA-dependent RNA polymerase, is encoded by all known picornaviruses, and their structures are highly conserved. In the process of picornavirus replication, 3D polymerase facilitates the assembly of replication complexes and directly catalyzes the synthesis of viral RNA. The nuclear localization signal carried by picornavirus 3D polymerase, combined with its ability to interact with other viral proteins, viral RNA and cellular proteins, indicate that its noncatalytic role is equally important in viral infections. Recent studies have shown that 3D polymerase has multiple effects on host cell biological functions, including inducing cell cycle arrest, regulating host cell translation, inducing autophagy, evading immune responses, and triggering inflammasome formation. Thus, 3D polymerase would be a very valuable target for the development of antiviral therapies. This review summarizes current studies on the structure of 3D polymerase and its regulation of host cell responses, thereby improving the understanding of picornavirus-mediated pathogenesis caused by 3D polymerase.

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“…Tenovin-1 derivative AcTU showed broad-spectrum resistance against enteroviruses such as EV-A71, EV-D68, CVA16, CVA21, and CVB1. Mechanistically, AcTU inhibited viral replication by targeting 3D pol , and excitingly, in vivo experiments demonstrated that oral administration of AcTU at 0.6 mg/kg/d to mice was highly protective against lethal EV-A71 attack [ 139 ]. Jeong et al found 2-amino-4-arylthiazole targets FMDV 3D pol by high throughput screening (HTS) adapting fluorescence polarization (FP), and in vitro evaluations of its derivatives 20i and 24a showed more effective inhibition of FMDV [ 140 ].…”

Section: Drugs Acting On 3d Polmentioning

confidence: 99%

The multiple roles of viral 3D ^pol protein in picornavirus infections

Nie,

Zhai,

Zhang

et al. 2024

Virulence

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The Picornaviridae are a large group of positive-sense, single-stranded RNA viruses, and most research has focused on the Enterovirus genus, given they present a severe health risk to humans. Other picornaviruses, such as foot-and-mouth disease virus (FMDV) and senecavirus A (SVA), affect agricultural production with high animal mortality to cause huge economic losses. The 3D pol protein of picornaviruses is widely known to be used for genome replication; however, a growing number of studies have demonstrated its non-polymerase roles, including modulation of host cell biological processes, viral replication complex assembly and localization, autophagy, and innate immune responses. Currently, there is no effective vaccine to control picornavirus diseases widely, and clinical therapeutic strategies have limited efficiency in combating infections. Many efforts have been made to develop different types of drugs to prohibit virus survival; the most important target for drug development is the virus polymerase, a necessary element for virus replication. For picornaviruses, there are also active efforts in targeted 3D pol drug development. This paper reviews the interaction of 3D pol proteins with the host and the progress of drug development targeting 3D pol .

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Identification of a novel acylthiourea-based potent broad-spectrum inhibitor for enterovirus 3D polymerase in vitro and in vivo

Cited by 8 publications

References 43 publications

Novel Acyl Thiourea-Based Hydrophobic Tagging Degraders Exert Potent Anti-Influenza Activity through Two Distinct Endonuclease Polymerase Acidic-Targeted Degradation Pathways

Novel Acyl Thiourea-Based Hydrophobic Tagging Degraders Exert Potent Anti-Influenza Activity through Two Distinct Endonuclease Polymerase Acidic-Targeted Degradation Pathways

Multiple functions of the nonstructural protein 3D in picornavirus infection

The multiple roles of viral 3D ^pol protein in picornavirus infections

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Identification of a novel acylthiourea-based potent broad-spectrum inhibitor for enterovirus 3D polymerase in vitro and in vivo

Cited by 8 publications

References 43 publications

Novel Acyl Thiourea-Based Hydrophobic Tagging Degraders Exert Potent Anti-Influenza Activity through Two Distinct Endonuclease Polymerase Acidic-Targeted Degradation Pathways

Novel Acyl Thiourea-Based Hydrophobic Tagging Degraders Exert Potent Anti-Influenza Activity through Two Distinct Endonuclease Polymerase Acidic-Targeted Degradation Pathways

Multiple functions of the nonstructural protein 3D in picornavirus infection

The multiple roles of viral 3D pol protein in picornavirus infections

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The multiple roles of viral 3D ^pol protein in picornavirus infections