Small molecule inhibitor E-64 exhibiting the activity against African swine fever virus pS273R

Liu, Bangzuo; Cui, Yuesong; Liu, Gen; Wei, Shu; Yang, Zuofeng; Du, Fangyuan; An, Tongqing; Liu, Jinling; Shen, Guoshun; Chen, Zeliang

doi:10.1016/j.bmc.2021.116055

Cited by 10 publications

(8 citation statements)

References 31 publications

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“…Its complex viral structure and unexplained infection mechanisms have greatly hindered the development of vaccines and specific antiviral drugs. Several anti-ASFV small molecule compounds were synthesized and evaluated, for example, the ASFV pS273R inhibitor E-64 and microtubule-stabilizing agent compound 6b [29,30]. However, the ASFV encodes 68 structural proteins and more than 100 non-structural proteins and regulates multiple cellular biological processes to finish its life-cycle [31].…”

Section: Discussionmentioning

confidence: 99%

Berbamine Hydrochloride Inhibits African Swine Fever Virus Infection In Vitro

et al. 2022

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African swine fever virus (ASFV) causes a viral disease in swine with a mortality rate of approximately 100%, threatening the global pig industry's economic development. However, vaccines are not yet commercially available, and other antiviral therapeutics, such as antiviral drugs, are urgently needed. In this study, berbamine hydrochloride, a natural bis-benzylisoquinoline alkaloid isolated from the traditional Chinese herb Berberis amurensis, showed significant antiviral activity against ASFV. The 50% cytotoxic concentration (CC50) of berbamine hydrochloride in porcine alveolar macrophages (PAMs) was 27.89 μM. The antiviral activity assay demonstrated that berbamine hydrochloride inhibits ASFV in a dose-dependent manner. In addition, a 4.14 log TCID50 decrease in the viral titre resulting from non-cytotoxic berbamine hydrochloride was found. Moreover, the antiviral activity of berbamine hydrochloride was maintained for 48h and took effect at multiplicities of infection (MOI) of 0.01, 0.1, and 1. The time-of-addition analysis revealed an inhibitory effect throughout the entire virus life-cycle. A subsequent viral entry assay verified that berbamine hydrochloride blocks the early stage of ASFV infection. Moreover, similar anti-ASFV activity of berbamine hydrochloride was also found in PK-15 and 3D4/21 cells. In summary, these results indicate that berbamine hydrochloride is an effective anti-ASFV natural product and may be considered a novel antiviral drug.

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Section: Discussionmentioning

confidence: 99%

Berbamine Hydrochloride Inhibits African Swine Fever Virus Infection In Vitro

et al. 2022

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“…The structural differences between pS273R and other proteases make pS273R an attractive target for the development of drugs against ASFV. Indeed, previous work has shown that reduced expression of pS273R inhibited polyprotein processing, and significantly reduced infectious virus production [ 6 , 7 , 8 ]. In addition, researchers have found that gasdermin D (GSDMD) can also be cut by ASFV pS273R.…”

Section: Introductionmentioning

confidence: 99%

“…Despite ongoing efforts, there are currently no effective drugs for the treatment of ASF, several molecules have been identified as having inhibitory activity against the pS273R protein of the ASFV. These include a group of peptide inhibitors based on the human SUMO-1 substrate complex (RCSB_PDB: 1TGZ) that contain an electrophilic warhead (-CHO), and the defensin-like peptide toxin OPTX-1 and the small molecule inhibitor E64 [ 7 , 12 ]. The peptide inhibitor taking the CHO group contains a carbonyl carbon, which is an electrophilic group capable of attracting electrons from nucleophilic groups.…”

Section: Introductionmentioning

confidence: 99%

Structural Analysis, Multi-Conformation Virtual Screening and Molecular Simulation to Identify Potential Inhibitors Targeting pS273R Proteases of African Swine Fever Virus

Liu

Zhang

et al. 2023

Molecules

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The African Swine Fever virus (ASFV) causes an infectious viral disease in pigs of all ages. The development of antiviral drugs primarily aimed at inhibition of proteases required for the proteolysis of viral polyproteins. In this study, the conformation of the pS273R protease in physiological states were investigated, virtually screened the multi-protein conformation of pS273R target proteins, combined various molecular docking scoring functions, and identified five potential drugs from the Food and Drug Administration drug library that may inhibit pS273R. Subsequent validation of the dynamic interactions of pS273R with the five putative inhibitors was achieved using molecular dynamics simulations and binding free energy calculations using the molecular mechanics/Poison-Boltzmann (Generalized Born) (MM/PB(GB)SA) surface area. These findings demonstrate that the arm domain and Thr159-Lys167 loop region of pS273R are significantly more flexible compared to the core structural domain, and the Thr159-Lys167 loop region can serve as a “gatekeeper” in the substrate channel. Leucovorin, Carboprost, Protirelin, Flavin Mononucleotide, and Lovastatin Acid all have Gibbs binding free energies with pS273R that were less than −20 Kcal/mol according to the MM/PBSA analyses. In contrast to pS273R in the free energy landscape, the inhibitor and drug complexes of pS273R showed distinct structural group distributions. These five drugs may be used as potential inhibitors of pS273R and may serve as future drug candidates for treating ASFV.

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“…Alternatively, genistein and fluoroquinolones, such as enrofloxacin, were found to impair viral genome replication by inhibiting the ASFV type II topoisomerase ( 21 – 23 ). Viral protease inhibitors OPTX-1 and E-64 inhibit the activity of S273R, a highly conserved ASFV protease of the SUMO-1 cysteine protease family, impairing ASFV replication ( 24 , 25 ). Other inhibitors of ASFV replication have also been described but the viral or cellular targets have not been fully defined.…”

Section: Introductionmentioning

confidence: 99%