Development of potent dipeptide-type SARS-CoV 3CL protease inhibitors with novel P3 scaffolds: Design, synthesis, biological evaluation, and docking studies

Pillaiyar, Thanigaimalai; Konno, Sho; Yamamoto, Takehito; Koiwai, Yuji; Taguchi, Akihiro; Takayama, Kentaro; Yakushiji, Fumika; Akaji, Kenichi; Chen, Shen En; Naser‐Tavakolian, Aurash; Schön, Arne; Freire, Ernesto; Hayashi, Yoshio

doi:10.1016/j.ejmech.2013.07.037

Cited by 81 publications

(94 citation statements)

References 26 publications

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“…Moreover, we showed that co-infection with a wild type virus rescued the replication of the replication-deficient SARS-CoV carrying a mutation in nsp4, suggesting that the membrane rearrangements inducing by the nsp3-nsp4 interaction are necessary to provide a site for the viral genome replication. Two cysteine proteases, nsp3 and nsp5 of SARS-CoV, participate in processing of the polyprotein to release other nsps, and chemical compounds that have been shown to suppress the proteinase activities (Konno et al, 2016;Ratia et al, 2008;Thanigaimalai et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Two-amino acids change in the nsp4 of SARS coronavirus abolishes viral replication

Sakai

Kawachi²,

Terada³

et al. 2017

Virology

140

126

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Infection with coronavirus rearranges the host cell membrane to assemble a replication/transcription complex in which replication of the viral genome and transcription of viral mRNA occur. Although coexistence of nsp3 and nsp4 is known to cause membrane rearrangement, the mechanisms underlying the interaction of these two proteins remain unclear. We demonstrated that binding of nsp4 with nsp3 is essential for membrane rearrangement and identified amino acid residues in nsp4 responsible for the interaction with nsp3. In addition, we revealed that the nsp3-nsp4 interaction is not sufficient to induce membrane rearrangement, suggesting the participation of other factors such as host proteins. Finally, we showed that loss of the nsp3-nsp4 interaction eliminated viral replication by using an infectious cDNA clone and replicon system of SARS-CoV. These findings provide clues to the mechanism of the replication/transcription complex assembly of SARS-CoV and could reveal an antiviral target for the treatment of betacoronavirus infection.

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Section: Discussionmentioning

confidence: 99%

Two-amino acids change in the nsp4 of SARS coronavirus abolishes viral replication

Sakai

Kawachi²,

Terada³

et al. 2017

Virology

140

126

View full text Add to dashboard Cite

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“…Accordingly, compounds 9 and 10 displayed the best inhibitory potencies against 3CLpro ( K i values of 0.39 and 0.33 μM, respectively) . Further studies led to the identification of a rigid indole‐2‐carbonyl unit as one of the best P3 moieties, thus providing inhibitor 11 ( K i =0.065 μM) …”

Section: Cov Protease Inhibitorsmentioning

confidence: 98%

Drug Development and Medicinal Chemistry Efforts toward SARS‐Coronavirus and Covid‐19 Therapeutics

et al. 2020

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The COVID‐19 pandemic caused by SARS‐CoV‐2 infection is spreading at an alarming rate and has created an unprecedented health emergency around the globe. There is no effective vaccine or approved drug treatment against COVID‐19 and other pathogenic coronaviruses. The development of antiviral agents is an urgent priority. Biochemical events critical to the coronavirus replication cycle provided a number of attractive targets for drug development. These include, spike protein for binding to host cell‐surface receptors, proteolytic enzymes that are essential for processing polyproteins into mature viruses, and RNA‐dependent RNA polymerase for RNA replication. There has been a lot of ground work for drug discovery and development against these targets. Also, high‐throughput screening efforts have led to the identification of diverse lead structures, including natural product‐derived molecules. This review highlights past and present drug discovery and medicinal‐chemistry approaches against SARS‐CoV, MERS‐CoV and COVID‐19 targets. The review hopes to stimulate further research and will be a useful guide to the development of effective therapies against COVID‐19 and other pathogenic coronaviruses.

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“…10 Unfortunately, to date, no protease inhibitors targeting SARS-CoV 3CL Mpro have been FDA-approved, despite significant research effort during the past fifteen years. [11][12][13][14][15][16][17] The 3CL M pro structure is composed of three domains. 18,19 Domains I (residues 8-101) and II (residues 102-184) are composed of antiparallel β-barrel structures and are the catalytic domains.…”

Section: Main Textmentioning

confidence: 99%

Structural Plasticity of the SARS-CoV-2 3CL Mpro Active Site Cavity Revealed by Room Temperature X-ray Crystallography

Kneller

Phillips

O’Neill

et al. 2020

Preprint

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The COVID-19 disease caused by the SARS-CoV-2 Coronavirus has become a pandemic health crisis. An attractive target for antiviral inhibitors is the main protease 3CL Mpro due to its essential role in processing the polyproteins translated from viral RNA. Here we report the room temperature X-ray structure of unliganded SARS-CoV-2 3CL Mpro, revealing the resting structure of the active site and the conformation of the catalytic site cavity. Comparison with previously reported low-temperature ligand-free and inhibitor-bound structures suggest that the room temperature structure may provide more relevant information at physiological temperatures for aiding in molecular docking studies.

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Development of potent dipeptide-type SARS-CoV 3CL protease inhibitors with novel P3 scaffolds: Design, synthesis, biological evaluation, and docking studies

Cited by 81 publications

References 26 publications

Two-amino acids change in the nsp4 of SARS coronavirus abolishes viral replication

Two-amino acids change in the nsp4 of SARS coronavirus abolishes viral replication

Drug Development and Medicinal Chemistry Efforts toward SARS‐Coronavirus and Covid‐19 Therapeutics

Structural Plasticity of the SARS-CoV-2 3CL Mpro Active Site Cavity Revealed by Room Temperature X-ray Crystallography

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