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Dive into the research topics where Jun Takayama is active.

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Featured researches published by Jun Takayama.


Journal of Virology | 2010

Deubiquitinating and Interferon Antagonism Activities of Coronavirus Papain-Like Proteases

Mark A. Clementz; Zhongbin Chen; Bridget S. Banach; Yanhua Wang; Li Sun; Kiira Ratia; Yahira M. Báez-Santos; Jie Wang; Jun Takayama; Arun K. Ghosh; Kui Li; Andrew D. Mesecar; Susan C. Baker

ABSTRACT Coronaviruses encode multifunctional proteins that are critical for viral replication and for blocking the innate immune response to viral infection. One such multifunctional domain is the coronavirus papain-like protease (PLP), which processes the viral replicase polyprotein, has deubiquitinating (DUB) activity, and antagonizes the induction of type I interferon (IFN). Here we characterized the DUB and IFN antagonism activities of the PLP domains of human coronavirus NL63 and severe acute respiratory syndrome (SARS) coronavirus to determine if DUB activity mediates interferon antagonism. We found that NL63 PLP2 deconjugated ubiquitin (Ub) and the Ub-line molecule ISG15 from cellular substrates and processed both lysine-48- and lysine-63- linked polyubiquitin chains. This PLP2 DUB activity was dependent on an intact catalytic cysteine residue. We demonstrated that in contrast to PLP2 DUB activity, PLP2-mediated interferon antagonism did not require enzymatic activity. Furthermore, addition of an inhibitor that blocks coronavirus protease/DUB activity did not abrogate interferon antagonism. These results indicated that a component of coronavirus PLP-mediated interferon antagonism was independent of protease and DUB activity. Overall, these results demonstrate the multifunctional nature of the coronavirus PLP domain as a viral protease, DUB, and IFN antagonist and suggest that these independent activities may provide multiple targets for antiviral therapies.


Proceedings of the National Academy of Sciences of the United States of America | 2008

A noncovalent class of papain-like protease/deubiquitinase inhibitors blocks SARS virus replication

Kiira Ratia; Scott D. Pegan; Jun Takayama; Katrina Sleeman; Melissa Coughlin; Surendranath Baliji; Rima Chaudhuri; Wentao Fu; Bellur S. Prabhakar; Michael E. Johnson; Susan C. Baker; Arun K. Ghosh; Andrew D. Mesecar

We report the discovery and optimization of a potent inhibitor against the papain-like protease (PLpro) from the coronavirus that causes severe acute respiratory syndrome (SARS-CoV). This unique protease is not only responsible for processing the viral polyprotein into its functional units but is also capable of cleaving ubiquitin and ISG15 conjugates and plays a significant role in helping SARS-CoV evade the human immune system. We screened a structurally diverse library of 50,080 compounds for inhibitors of PLpro and discovered a noncovalent lead inhibitor with an IC50 value of 20 μM, which was improved to 600 nM via synthetic optimization. The resulting compound, GRL0617, inhibited SARS-CoV viral replication in Vero E6 cells with an EC50 of 15 μM and had no associated cytotoxicity. The X-ray structure of PLpro in complex with GRL0617 indicates that the compound has a unique mode of inhibition whereby it binds within the S4-S3 subsites of the enzyme and induces a loop closure that shuts down catalysis at the active site. These findings provide proof-of-principle that PLpro is a viable target for development of antivirals directed against SARS-CoV, and that potent noncovalent cysteine protease inhibitors can be developed with specificity directed toward pathogenic deubiquitinating enzymes without inhibiting host DUBs.


Journal of Medicinal Chemistry | 2010

Severe Acute Respiratory Syndrome-Coronavirus Papain-Like Novel Protease Inhibitors: Design, Synthesis, Protein-Ligand X-ray Structure and Biological Evaluation

Arun K. Ghosh; Jun Takayama; Kalapala Venkateswara Rao; Kiira Ratia; Rima Chaudhuri; Debbie C. Mulhearn; Hyun Lee; Daniel B. Nichols; Surendranath Baliji; Susan C. Baker; Michael E. Johnson; Andrew D. Mesecar

The design, synthesis, X-ray crystal structure, molecular modeling, and biological evaluation of a series of new generation SARS-CoV PLpro inhibitors are described. A new lead compound 3 (6577871) was identified via high-throughput screening of a diverse chemical library. Subsequently, we carried out lead optimization and structure-activity studies to provide a series of improved inhibitors that show potent PLpro inhibition and antiviral activity against SARS-CoV infected Vero E6 cells. Interestingly, the (S)-Me inhibitor 15 h (enzyme IC(50) = 0.56 microM; antiviral EC(50) = 9.1 microM) and the corresponding (R)-Me 15 g (IC(50) = 0.32 microM; antiviral EC(50) = 9.1 microM) are the most potent compounds in this series, with nearly equivalent enzymatic inhibition and antiviral activity. A protein-ligand X-ray structure of 15 g-bound SARS-CoV PLpro and a corresponding model of 15 h docked to PLpro provide intriguing molecular insight into the ligand-binding site interactions.


Journal of Medicinal Chemistry | 2009

Structure-based design, synthesis, and biological evaluation of a series of novel and reversible inhibitors for the severe acute respiratory syndrome-coronavirus papain-like protease.

Arun K. Ghosh; Jun Takayama; Yoann Aubin; Kiira Ratia; Rima Chaudhuri; Yahira Baez; Katrina Sleeman; Melissa Coughlin; Daniel B. Nichols; Debbie C. Mulhearn; Bellur S. Prabhakar; Susan C. Baker; Michael E. Johnson; Andrew D. Mesecar

We describe here the design, synthesis, molecular modeling, and biological evaluation of a series of small molecule, nonpeptide inhibitors of SARS-CoV PLpro. Our initial lead compound was identified via high-throughput screening of a diverse chemical library. We subsequently carried out structure-activity relationship studies and optimized the lead structure to potent inhibitors that have shown antiviral activity against SARS-CoV infected Vero E6 cells. Upon the basis of the X-ray crystal structure of inhibitor 24-bound to SARS-CoV PLpro, a drug design template was created. Our structure-based modification led to the design of a more potent inhibitor, 2 (enzyme IC(50) = 0.46 microM; antiviral EC(50) = 6 microM). Interestingly, its methylamine derivative, 49, displayed good enzyme inhibitory potency (IC(50) = 1.3 microM) and the most potent SARS antiviral activity (EC(50) = 5.2 microM) in the series. We have carried out computational docking studies and generated a predictive 3D-QSAR model for SARS-CoV PLpro inhibitors.


Organic and Biomolecular Chemistry | 2008

Potent HIV-1 protease inhibitors incorporating meso-bicyclic urethanes as P2-ligands: structure-based design, synthesis, biological evaluation and protein–ligand X-ray studies

Arun K. Ghosh; Sandra Gemma; Jun Takayama; Abigail Baldridge; Sofiya Leshchenko-Yashchuk; Heather Miller; Yuan Fang Wang; Andrey Kovalevsky; Yashiro Koh; Irene T. Weber; Hiroaki Mitsuya

Recently, we designed a series of novel HIV-1 protease inhibitors incorporating a stereochemically defined bicyclic fused cyclopentyl (Cp-THF) urethane as the high affinity P2-ligand. Inhibitor with this P2-ligand has shown very impressive potency against multi-drug-resistant clinical isolates. Based upon the -bound HIV-1 protease X-ray structure, we have now designed and synthesized a number of meso-bicyclic ligands which can conceivably interact similarly to the Cp-THF ligand. The design of meso-ligands is quite attractive as they do not contain any stereocenters. Inhibitors incorporating urethanes of bicyclic-1,3-dioxolane and bicyclic-1,4-dioxane have shown potent enzyme inhibitory and antiviral activities. Inhibitor (K(i) = 0.11 nM; IC(50) = 3.8 nM) displayed very potent antiviral activity in this series. While inhibitor showed comparable enzyme inhibitory activity (K(i) = 0.18 nM) its antiviral activity (IC(50) = 170 nM) was significantly weaker than inhibitor . Inhibitor maintained an antiviral potency against a series of multi-drug resistant clinical isolates comparable to amprenavir. A protein-ligand X-ray structure of -bound HIV-1 protease revealed a number of key hydrogen bonding interactions at the S2-subsite. We have created an active model of inhibitor based upon this X-ray structure.


Bioorganic & Medicinal Chemistry Letters | 2015

Structure-based design, synthesis, X-ray studies, and biological evaluation of novel HIV-1 protease inhibitors containing isophthalamide-derived P2-ligands

Arun K. Ghosh; Jun Takayama; Luke A. Kassekert; Jean Rene Ella-Menye; Sofiya Yashchuk; Johnson Agniswamy; Yuan Fang Wang; Manabu Aoki; Masayuki Amano; Irene T. Weber; Hiroaki Mitsuya

We describe the design, synthesis and biological evaluation of a series of novel HIV-1 protease inhibitors bearing isophthalamide derivatives as the P2-P3 ligands. We have investigated a range of acyclic and heterocyclic amides as the extended P2-P3 ligands. These inhibitors displayed good to excellent HIV-1 protease inhibitory activity. Also, a number of inhibitors showed very good antiviral activity in MT cells. Compound 5n has shown an enzyme Ki of 0.17 nM and antiviral IC50 of 14 nM. An X-ray crystal structure of inhibitor 5o-bound to HIV-1 protease was determined at 1.11Å resolution. This structure revealed important molecular insight into the inhibitor-HIV-1 protease interactions in the active site.


Bioorganic & Medicinal Chemistry | 2017

Design of novel HIV-1 protease inhibitors incorporating isophthalamide-derived P2-P3 ligands: Synthesis, biological evaluation and X-ray structural studies of inhibitor-HIV-1 protease complex.

Arun K. Ghosh; Margherita Brindisi; Prasanth R. Nyalapatla; Jun Takayama; Jean Rene Ella-Menye; Sofiya Yashchuk; Johnson Agniswamy; Yuan Fang Wang; Manabu Aoki; Masayuki Amano; Irene T. Weber; Hiroaki Mitsuya

Based upon molecular insights from the X-ray structures of inhibitor-bound HIV-1 protease complexes, we have designed a series of isophthalamide-derived inhibitors incorporating substituted pyrrolidines, piperidines and thiazolidines as P2-P3 ligands for specific interactions in the S2-S3 extended site. Compound 4b has shown an enzyme Ki of 0.025nM and antiviral IC50 of 69nM. An X-ray crystal structure of inhibitor 4b-HIV-1 protease complex was determined at 1.33Å resolution. We have also determined X-ray structure of 3b-bound HIV-1 protease at 1.27Å resolution. These structures revealed important molecular insight into the inhibitor-HIV-1 protease interactions in the active site.


Cell & Bioscience | 2017

A fission yeast cell-based system for multidrug resistant HIV-1 proteases

Zsigmond Benko; Dong Liang; Ge Li; Robert T. Elder; Anindya Sarkar; Jun Takayama; Arun K. Ghosh; Richard Y. Zhao

BackgroundHIV-1 protease (PR) is an essential enzyme for viral production. Thus, PR inhibitors (PIs) are the most effective class of anti-HIV drugs. However, the main challenge to the successful use of PI drugs in patient treatment is the emergence of multidrug resistant PRs (mdrPRs). This study aimed to develop a fission yeast cell-based system for rapid testing of new PIs that combat mdrPRs.ResultsThree mdrPRs were isolated from HIV-infected patients that carried seven (M7PR), ten (M10PR) and eleven (M11PR) PR gene mutations, respectively. They were cloned and expressed in fission yeast under an inducible promoter to allow the measurement of PR-specific proteolysis and drug resistance. The results showed that all three mdrPRs maintained their abilities to proteolyze HIV viral substrates (MA↓CA and p6) and to confer drug resistance. Production of these proteins in the fission yeast caused cell growth inhibition, oxidative stress and altered mitochondrial morphologies that led to cell death. Five investigational PIs were used to test the utility of the established yeast system with an FDA-approved PI drug Darunavir (DRV) as control. All six compounds suppressed the wildtype PR (wtPR) and the M7PR-mediated activities. However, none of them were able to suppress the M10PR or the M11PR.ConclusionsThe three clinically isolated mdrPRs maintained their viral proteolytic activities and drug resistance in the fission yeast. Furthermore, those viral mdrPR activities were coupled with the induction of growth inhibition and cell death, which could be used to test the PI activities. Indeed, the five investigational PIs and DRV suppressed the wtPR in fission yeast as they did in mammalian cells. Significantly, two of the high level mdrPRs (M10PR and M11PR) were resistant to all of the existing PI drugs including DRV. This observation underscores the importance of continued searching for new PIs against mdrPRs.


Tetrahedron Letters | 2008

Enantioselective synthesis of cyclopentyltetrahydrofuran (Cp-THF), an important high-affinity P2-ligand for HIV-1 protease inhibitors

Arun K. Ghosh; Jun Takayama


Archive | 2009

Compounds and methods for treating respiratory diseases

Arun K. Ghosh; Jun Takayama; Andrew D. Mesecar; Michael E. Johnson; Kiira M. Ratia; Rima Chaudhuri; Debbie C. Mulhearn

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Andrew D. Mesecar

University of Illinois at Chicago

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Kiira Ratia

University of Illinois at Chicago

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Michael E. Johnson

University of Illinois at Chicago

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Susan C. Baker

Loyola University Chicago

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Debbie C. Mulhearn

University of Illinois at Chicago

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Irene T. Weber

Georgia State University

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Yuan Fang Wang

Georgia State University

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