Structure of the HRV-C 3C-Rupintrivir Complex Provides New Insights for Inhibitor Design

Yuan, Shuai; Fan, Kaiyue; Chen, Zhonghao; Sun, Yao; Hou, Hai; Zhu, Ling

doi:10.1007/s12250-020-00196-4

Cited by 14 publications

(17 citation statements)

References 39 publications

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“…To analyze the conservation of mutation sites in FMDV by sequence alignment, the sequences of 43 strains of O-type FMDV and 9 strains from other serotypes (A, C, AsiaI and SAT serotype) on May 30, 2021 by guest http://jvi.asm.org/ Downloaded from were download from PubMed. WebLogo generates sequence logos was used to a more detailed description of sequence similarity and rapidly reveal significant features of the alignment (http://weblogo.berkeley.edu/logo.cgi) (55,56).…”

Section: Multiple Sequence Alignmentmentioning

confidence: 99%

A Heat-Induced Mutation on VP1 of Foot-and-Mouth Disease Virus Serotype O Enhanced Capsid Stability and Immunogenicity

Dong

Zhang

et al. 2021

J Virol

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Foot-and-mouth disease (FMD) is a highly contagious viral disease affecting cloven-hoofed animals that cause a significant economic burden globally. Vaccination is the most effective FMD control strategy. However, FMDV particles are prone to dissociate when appropriate physical or chemical conditions are unavailable, such as an incomplete cold chain. Such degraded vaccines result in compromised herd vaccination. Therefore, thermostable FMD particles are needed for use in vaccines. This study generated thermostable FMDV mutants (M3 and M10) by serial passages at high temperature, subsequent amplification, and purification. Both mutants contained an alanine to threonine mutation at position 13 in VP1 (A1013T), although M3 contained 3 additional mutations. The selected mutants showed improved stability and immunogenicity in neutralizing antibody titers, compared with the wild-type (wt) virus. The sequencing analysis and cryo-electron microscopy showed that the mutation of alanine to threonine at the 13th amino acid (aa) in VP1 protein (A1013T) is critical for the capsid stability of FMDV. Virus-like particles (VLPA1013T) containing A1013T also showed significantly improved stability to heat treatment. This study demonstrated that Thr at the 13th amino acid of VP1 could stabilize the capsid of FMDV. Our findings will facilitate the development of a stable vaccine against FMDV serotype O. IMPORTANCE Foot-and-mouth disease (FMD) serotype O is one of the global epidemic serotypes, and cause significant economic loss. Vaccination plays a key role in the prevention and control of FMD. However, the success of vaccination mainly depends on the quality of the vaccine. Here, the thermostable FMDV mutants (M3 and M10) were selected through thermal-screening at high temperatures with improved stability and immunogenicity compared to the wild-type virus. The results of multi-sequence alignment and Cryo-EM analysis showed that the "Thr" substitution at the 13th amino acid in VP1 protein is critical for the capsid stability of FMDV. For thermolabile type O FMDV, this major discovery will aid the development of its thermostable vaccine.

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Section: Multiple Sequence Alignmentmentioning

confidence: 99%

A Heat-Induced Mutation on VP1 of Foot-and-Mouth Disease Virus Serotype O Enhanced Capsid Stability and Immunogenicity

Dong

Zhang

et al. 2021

J Virol

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“…[46][47][48] Although Scheme 21 looks inviting in terms of step count, it is not financially viable in preparing compound 3,6-dichloropyrazine-2carbonitrile (82) because of the low yield and the high cost involved in the process. Zhang et al [49-(b)] also reported a new method for the preparation of favipiravir ( 79) from 3-hydroxypyrazine-2-carboxylic acid (91), which was esterified and amidated to give 3-hydroxypyrazine-2-carboxamide (80). Its 6-nitro derivative 81 was obtained on its nitration with potassium nitrate + H 2 SO 4 .…”

Section: Synthesis Of Favipiravir (79)mentioning

confidence: 99%

“…Rupintrivir (AG-7088, Rupinavir) is a peptidomimetic antiviral drug that acts as a 3C and 3CL protease inhibitor. [89][90][91] It was developed for the treatment of rhinoviruses, [92,93] and has subsequently been investigated for the treatment of other viral diseases including those caused by picornaviruses, [94,95] norovirus, [96] and coronaviruses, such as SARS and COVID-19. [97,98]…”

Section: Rupintrivirmentioning

confidence: 99%

A comprehensive update on the structure and synthesis of potential drug targets for combating the coronavirus pandemic caused by SARS‐CoV‐2

Malik

Jain

et al. 2022

Archiv der Pharmazie

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The outbreak of the coronavirus pandemic COVID-19 created by its severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) variant, known for producing a very severe acute respiratory syndrome, has created an unprecedented situation by its continual assault around the world. The crisis caused by the SARS-CoV-2 variant has been a global challenge, calling to mitigate this unprecedented pandemic that has engulfed the whole world. Since the outbreak and spread of COVID-19, many researchers globally have been grappling to find new clinically trialed active drugs with anti-COVID-19 activity, from antimalarial drugs to JAK inhibitors, antiviral drugs, immune suppressants, and so forth. This article presents a brief discussion on the activity and synthesis of some active molecules such as favipiravir, hydroxychloroquine, pirfenidone, remdesivir, lopinavir, camostat, chloroquine, baricitinib, molnupiravir, and so forth, which are under trial.

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“…It remains to be seen how inhibitors revealed by this novel technology compare to those already available, such as rupintrivir (ref. [105] and reviewed in refs. [106,107]).…”

Section: Targeting Non-structural Viral Proteinsmentioning

confidence: 99%

Rhinovirus Inhibitors: Including a New Target, the Viral RNA

Real-Hohn

Blaas

2021

Viruses

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Rhinoviruses (RVs) are the main cause of recurrent infections with rather mild symptoms characteristic of the common cold. Nevertheless, RVs give rise to enormous numbers of absences from work and school and may become life-threatening in particular settings. Vaccination is jeopardised by the large number of serotypes eliciting only poorly cross-neutralising antibodies. Conversely, antivirals developed over the years failed FDA approval because of a low efficacy and/or side effects. RV species A, B, and C are now included in the fifteen species of the genus Enteroviruses based upon the high similarity of their genome sequences. As a result of their comparably low pathogenicity, RVs have become a handy model for other, more dangerous members of this genus, e.g., poliovirus and enterovirus 71. We provide a short overview of viral proteins that are considered potential drug targets and their corresponding drug candidates. We briefly mention more recently identified cellular enzymes whose inhibition impacts on RVs and comment novel approaches to interfere with infection via aggregation, virus trapping, or preventing viral access to the cell receptor. Finally, we devote a large part of this article to adding the viral RNA genome to the list of potential drug targets by dwelling on its structure, folding, and the still debated way of its exit from the capsid. Finally, we discuss the recent finding that G‑quadruplex stabilising compounds impact on RNA egress possibly via obfuscating the unravelling of stable secondary structural elements.

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Structure of the HRV-C 3C-Rupintrivir Complex Provides New Insights for Inhibitor Design

Cited by 14 publications

References 39 publications

A Heat-Induced Mutation on VP1 of Foot-and-Mouth Disease Virus Serotype O Enhanced Capsid Stability and Immunogenicity

A Heat-Induced Mutation on VP1 of Foot-and-Mouth Disease Virus Serotype O Enhanced Capsid Stability and Immunogenicity

A comprehensive update on the structure and synthesis of potential drug targets for combating the coronavirus pandemic caused by SARS‐CoV‐2

Rhinovirus Inhibitors: Including a New Target, the Viral RNA

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